Substituted pyridines useful for inhibiting cholesteryl ester transfer protein activity

ABSTRACT

A class of substituted pyridines that are useful for inhibiting the activity of cholesteryl ester transfer protein, and have the structural formula (IA), wherein R2, R3, R4, R5, and R6 are defined in the claims.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This patent is a divisional of U.S. patent application Ser. No. 09/600,870 (filed Dec. 11, 2000, now U.S. Pat. No. 6,605,624 which, in turn, claims priority to International Patent Application No. PCT/US99/01871 (filed on Feb. 11, 1999; and published as International Publication No. WO 99/41237), which, in turn, claims priority to U.S. Provisional Patent Application Serial No. 60/074,586 (filed February 13, 1998). This patent also claims priority to U.S. Provisional Patent Application Serial No. 60/074,586. The entire text of each of the above-referenced patent applications is incorporated by reference into this patent.

FIELD OF THE INVENTION

This invention is in the field of preventing and/or treating cardiovascular disease, and specifically relates to compounds, compositions and methods for preventing and/or treating atherosclerosis and other coronary artery disease. More particularly, the invention relates to substituted pyridine compounds that inhibit cholesteryl ester transfer protein (CETP), also known as plasma lipid transfer protein-I.

BACKGROUND OF THEN INVENTION

Numerous studies have demonstrated that a low plasma concentration of high density lipoprotein (HDL) cholesterol is a powerful risk factor for the development of atherosclerosis (Barter and Rye, Atherosclerosis, 121, 1-12 (1996)). HDL is one of the major classes of lipoproteins that function in the transport of lipids through the blood. The major lipids found associated with HDL include cholesterol, cholesteryl ester, triglycerides, phospholipids and fatty acids. The other classes of lipoproteins found in the blood are low density lipoprotein (LDL) and very low density lipoprotein (VLDL). Since low levels of HDL cholesterol increase the risk of atherosclerosis, methods for elevating plasma HDL cholesterol would be therapeutically beneficial for the treatment of atherosclerosis and other diseases associated with accumulation of lipid in the blood vessels. These diseases include, but are not limited to, coronary heart disease, peripheral vascular disease, and stroke.

Atherosclerosis underlies most coronary artery disease (CAD), a major cause of morbidity and mortality in modern society. High LDL cholesterol (above 180 mg/dl) and low HDL cholesterol (below 35 mg/dl) have been shown to be important contributors to the development of atherosclerosis. Other diseases, such as peripheral vascular disease, stroke, and hypercholesterolaemia are negatively affected by adverse HDL/LDL ratios. Inhibition of CETP by the subject compounds are shown to effectively modify plasma HDL/LDL ratios, and to check the progress and/or formation of these diseases.

CETP is a plasma protein that facilitates the movement of cholesteryl esters and triglycerides between the various lipoproteins in the blood (Tall, J. Lipid Res., 34, 1255-74 (1993)). The movement of cholesteryl ester from HDL to LDL by CETP has the effect of lowering HDL cholesterol. It therefore follows that inhibition of CETP should lead to elevation of plasma HDL cholesterol and lowering of plasma LDL cholesterol, thereby providing a therapeutically beneficial plasma lipid profile (McCarthy, Medicinal Res. Revs., 13, 139-59 (1993)). This exact phenomenon was first demonstrated by Swenson et al., (J. Biol. Chem., 264, 14318 (1989)) with the use of a monoclonal antibody that specifically inhibited CETP. In rabbits, the antibody caused an elevation of the plasma HDL cholesterol and a decrease in LDL cholesterol. Son et al. (Biochim. Biophys. Acta 795, 743-480 (1984)) describes proteins from human plasma that +inhibit CETP. U.S. Pat. No. 5,519,001, issued to Kushwaha et al., describes a 36 amino acid peptide derived from baboon apo C-1 that inhibits CETP activity.

There have been several reports of compounds that act as CETP inhibitors. Barrett et al. (J. Am. Chem. Soc., 188, 7863-63 (1996)) describes cyclopropane-containing CETP inhibitors. Pietzonka et al. (Bioorg. Med. Chem. Lett, 6, 1951-54 (1996)) describe phosphonate-containing analogs of cholesteryl ester as CETP inhibitors. Coval et al. (Bioorg. Med. Chem. Lett., 5, 605-610 (1995)) describe Wiedendiol-A and -B, and related sesquiterpene compounds, as CETP inhibitors. Lee et al. (J. Antibiotics, 49, 693-96 (1996)) describe CETP inhibitors derived from an insect fungus. Busch et al. (Lipids, 25, 216-220, (1990)) describe cholesteryl acetyl bromide as a CETP inhibitor. Morton and Zilversmit (J. Lipid Res., 35, 836-47 (1982)) describe that p-chloromercuriphenyl sulfonate, p-hydroxymercuribenzoate and ethyl mercurithiosalicylate inhibit CETP. Bisgaier et al. (Lipids, 29, 811-8 (1994) describe 4-phenyl-5-tridecyl-4H-1,2,4-triazole-thiol as a CETP inhibitor.

A number of substituted pyridine compounds are known. For example, U.S. Pat. Nos. 4,609,399, 4,655,816; 4,692,184; 4,698,093; 4,789,395; 4,885,026; 4,936,905; 4,988,384; 5,037,469; 5,125,961; 5,129,943; 5,156,670; 5,169,432; and 5,260,262 each disclose novel substituted pyridines which are useful as herbicides and herbicide intermediates. No pharmacologic properties for the substituted pyridines are recited in these patents. Except as set forth below, the literature does not describe substituted pyridines as inhibitors of CETP.

Connolly et al. (Biochem. Biophys. Res. Comm. 223, 42-47 (1996)), describe 4,4′-dithiopyridine, 2,2′-dithiopyridine, 6,6′-dithionicotinic acid and 2,2′-dithiobis (pyridine-N-oxide) as CTEP inhibitors. The isolated pyridine compounds tested by Connolly et al. were, at best, inhibitory only after a 16 hour pre-incubation period and would not be useful in situations requiring rapid and potent inhibition. Connolly et al. also neither addressed whether substitution of the reported pyridines would increase their potency nor suggested the testing or use of specific substituted pyridines.

European Patent Application 796 846 A1 describes certain 2-aryl-substituted pyridines for use in the treatment of lipoproteinaemia and hyperlipoproteinaemia.

European Patent Application 818 197 A1 describes certain 2-aryl-substituted pyridines for use in the treatment of hyperlipoproteinaemia and atherosclerosis.

U.S. Pat. No. 4,925,852 describes 3-demethylmevalonic acid derivatives for use as inhibitors of cholesterol biosynthesis.

U.S. Pat. No. 5,169,857 describes 7-(polysubstituted pyridyl)-hept-6-endates for use in the treatment of hyperproteinaemia, lipoproteinaemia or arteriosclerosis.

WO 98/04528 describes certain 4-aryl-pyridyl compounds as anti-hypercholesterolemic, anti-hyperlipoproteinemic and anti-hyperglycemic agents.

SUMMARY OF THE INVENTION

The present invention is directed to a method for administering to a subject a therapeutically effective amount of a substituted pyridine of Formula I:

wherein:

R₂ and R₆ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R₂ and R₆ is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;

R₃ is selected from the group consisting of hydroxy, amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl,

—CHO,

—CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen, alkyl and cyanoalkyl; and

wherein R_(15a) is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy, and

R_(16a) is selected from the group consisting of alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, and heterocyclyl, arylalkoxy, trialkylsilyloxy;

R₄ is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloyloxy, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, heterocyclylamino, aryldialkylamino, diarylamino, diheteroarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, trialkylsilyl, trialkenylsilyl, triarylsilyl,

—OC(O)N(R_(8a)R_(8b)), wherein R_(8a) and R_(8b) are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,

—SO₂R₉, wherein R₉ is selected from the group consisting of hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,

—OP(O) (OR_(10a)) (OR_(10b)), wherein R_(10a) and R_(10b) are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and

—OP(S) (OR_(11a)) (OR_(11b)), wherein R_(11a) and R_(11b) are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

R₅ is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl, arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl, heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkenyl, alkenoxyalkenyl, alkynoxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl, heterocyclyloxyalkenyl, cyano, hydroxymethyl,

—CO₂R₁₄,

wherein R₁₄ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

wherein R_(15b) is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy, and

R_(16b) is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, and trialkylsilyloxy;

wherein R₁₇ and R₁₈ are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

wherein R₁₉ is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —SR₂₀, —OR₂₁, and —R₂₂CO₂R₂₃, wherein

R₂₀ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocyclyl, alkylheteroarylamino, arylheteroarylamino,

R₂₁ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl,

R₂₂ is selected from the group consisting of alkylene or arylene, and

R₂₃ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R₂₄ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, aralkenyl, and aralkynyl;

wherein R₂₅ is heterocyclylidenyl;

wherein R₂₆ and R₂₇ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R₂₈ and R₂₉ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R₃₀ and R₃₁ are independently alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy; and

wherein R₃₂ and R₃₃ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

 —C═C—Si(R₃₆)₃,

wherein R₃₆ is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl and heterocyclyl;

wherein R₃₇ and R₃₈ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R₃₉ is selected from the group consisting of hydrogen, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio, and

R₄₀ is selected from the group consisting of haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy, heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio;

—N═R₄₁,

wherein R₄₁ is heterocyclylidenyl;

wherein R₄₂ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, and

R₄₃ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, and haloheterocyclyl;

wherein R₄₄ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

—N═S═O;

—N═C═S;

—N═C═O;

—N₃;

 —SR₄₅,

wherein R₄₅ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl, aminocarbonylaryl, aminocarbonylheteroaryl, and aminocarbonylheterocyclyl, —SR₄₆, and —CH₂R₄₇,

wherein R₄₆ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and

R₄₇ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; and

wherein R₄₈ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and

R₄₉ is selected from the group consisting of alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;

wherein R₅₀ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy;

wherein R₅₁ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl; and

wherein R₅₃ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

or a pharmaceutically acceptable salt or tautomer thereof,

provided that when R₅ is selected from the group consisting of heterocyclylalkyl and heterocyclylalkenyl, then the heterocyclyl radical of the corresponding heterocyclylalkyl or heterocyclylalkenyl is other than a δ-lactone; and

provided that when R₄ is aryl, heteroaryl or heterocyclyl, and one of R₂ and R₆ is trifluoromethyl, then the other of R₂ and R₆ is difluoromethyl.

In another embodiment, the method involves the administration of a therapeutically effective amount of a substituted pyridine of Formula IA wherein:

R₂ and R₆ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R₂ and R₆ is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;

R₃ is selected from the group consisting of hydroxy, amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl,

—CO₂R₇,

wherein R₇ is selected from the group consisting of hydrogen, alkyl and cyanoalkyl; and

wherein R_(15a) is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, and

R_(16a) is selected from the group consisting of alkyl, aryl and heteroaryl;

R₄ is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, aralkoxy, alkoxycarbonyl, arylcarbonyloxy, thio, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, alkylamino, trialkylsilyl,

—OC(O)N(R₈)₂, wherein R₈ is aryl,

—SO₂R₉, wherein R₉ is aryl,

—OP(O) (OR₁₀)₂, wherein R₁₀ is alkyl, and

—OP(S) (OR₁₁)₂, wherein R₁₁ is alkyl;

R₅ is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, haloalkyl, alkynyl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylcarbonyloxyalkyl, heterocyclylalkyl, alkylthioalkyl, arylthioalkyl, heteroarylthioalkyl, alkoxyalkenyl, cyano, hydroxymethyl,

—CO₂R₁₄,

wherein R₁₄ is alkyl;

wherein R_(15b) is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio and alkoxy, and

R_(16b) is selected from the group consisting of alkyl, aryl and heteroaryl;

wherein R₁₇ and R₁₈ are independently alkyl;

wherein R₁₉ is selected from the group consisting of aryl, heteroaryl, —SR₂₀, —OR₂₁, and —R₂₂CO₂R₂₃,

wherein R₂₀ is selected from the group consisting of alkyl, aryl and aminoalkyl,

R₂₁ is aryl,

R₂₂ is alkylene, and

R₂₃ is alkyl;

wherein R₂₄ is selected from the group consisting of hydrogen, unsubstituted alkyl, and aralkyl;

wherein R₂₅ is heterocyclylidenyl;

wherein R₂₆ and R₂₇ are independently alkyl;

wherein R₂₈ and R₂₉ are independently alkyl;

wherein R₃₀ and R₃₁ are independently alkoxy;

wherein R₃₂ is selected from the group consisting of hydrogen and alkyl, and

R₃₃ is alkyl;

 —C≡C—Si(R₃₆)₃,

wherein R₃₆ is alkyl;

wherein R₃₇ and R₃₈ are independently alkyl;

wherein R₃₉ is selected from the group consisting of hydrogen, alkoxy, and alkylthio, and

R₄₀ is selected from the group consisting of haloalkyl, cycloalkyl, heterocyclylalkoxy, and alkylthio;

—N═R₄₁, wherein R₄₁ is heterocyclylidenyl;

wherein R₄₂ is selected from the group consisting of hydrogen and alkyl, and

R₄₃ is selected from the group consisting of cycloalkyl, chlorinated alkyl and substituted heteroaryl;

wherein R₄₄ is heteroaryl;

—N═S═O;

—N═C═S;

 —N═C═O;

—N₃;

—SR₄₅,

wherein R₄₅ is selected from the group consisting of hydrogen, alkyl, haloalkyl, heterocyclyl, aralkyl, heteroaralkyl, alkylthioalkyl, aminocarbonylalkyl, —SR₄₆, and —CH₂R₄₇,

wherein R₄₆ is selected from the group consisting of aryl and heteroaryl, and

R₄₇ is selected from the group consisting of aryl and heteroaryl; and

wherein R₄₈ is selected from the group consisting of hydrogen and alkyl, and

R₄₉ is selected from the group consisting of alkoxy and haloalkyl;

wherein R₅₀ is selected from the group consisting of alkyl, alkoxy, aryl and heteroaryl;

wherein R₅₁ is selected from the group consisting of haloalkyl and alkyl; and

wherein R₅₃ is aryl;

or a pharmaceutically acceptable salt or tautomer thereof,

provided that when R₅ is heterocyclylalkyl or heterocyclylalkenyl, then the heterocyclyl radical is other than a δ-lactone and the alkyl or alkenyl radical is other than —CH₂CH₂— or —CH═CH—.

Preferably, the immediately preceding embodiment involves the administration of a substituted pyridine of Formula IA as described above wherein:

when R₂ is difluoromethyl, R₃ is —CO₂CH₃, R₅ is

R₆ is trifluoromethyl and R₁₉ is the heteroaryl 1-pyrazolyl, then R₄ is other than isopropylamino; and

when R₂ is difluoromethyl, R₃ is —CO₂CH₃, R₅ is the unsubstituted heterocyclyl 2-(4,5-dihydro-oxazolyl), and R₆ is trifluoromethyl, then R₄ is other than cyclopropylmethyl; and

when R₂ and R₆ are selected from the group consisting of difluoromethyl and trifluoromethyl, R₃ is selected from the group consisting of —CO₂H and —CO₂C₂H₅, and R₅ is cyano, then R₄ is other than ethyl or —CH═C(CH₃)₂; and

when R₂ is methyl, R₃ is —CO₂C₂H₅, R₅ is

R₆ is methyl, and R₂₄ is —C(O)NHCH₂-(4-chlorophenyl), then R₄ is other than hydrogen; and

when R₂ is methyl, R₃ and R₅ are —CO₂C₂H₅, R₄ is i-propoxy, then R₆ is other than methyl; and

when R₂ is difluoromethyl, R₄ is —CH═C(CH₃)₂, R₅ is —CO₂CH₃, and R₆ is trifluoromethyl, then R₃ is other than —CO₂H; and

when R₂ is methyl, R₄ is hydrogen, R₅ is —CO₂C₂H₅, and R₆ is methyl, then R₃ is other than —CO₂C₂H₅;

when R₂ is difluoromethyl, R₄ is hydrogen, R₅ is —CO₂C₂H₅, and R₆ is trifluoromethyl, then R₃ is other than —CO₂C₂H₅;

when R₂ is difluoromethyl, R₄ is —CH₂SCH₃, R₅ is —CO₂C₂H₅, and R₆ is trifluoromethyl, then R₃ is other than —CO₂H;

when R₂ is trifluoromethyl, R₃ is —CO₂CH₃, R₄ is isobutyl, R₅ is —CO₂CH₃, then R₆ is other than methyl;

when R₂ is difluoromethyl, R₄ is selected from the group consisting of isopropyl and isobutyl, R₅ is —CO₂R₁₄, R₆ is trifluoromethyl, and R₁₄ is alkyl, then R₃ is other than amido;

when R₂ is selected from the group consisting of hydroxy and trifluoromethyl, R₄ and R₅ are hydrogen, and R₆ is selected from the group consisting of methyl and trifluoromethyl, then R₃ is other than —CO₂H;

when R₂ is selected from the group consisting of methyl, difluoromethyl and trifluoromethyl, R₃ is —CO₂CH₃, R₅ is hydrogen, and R₆ is selected from the group consisting of methyl and trifluoromethyl, then R₄ is other than alkyl or arylcarbonyloxy;

when R₂ is trifluoromethyl, R₃ is —CO₂C₂H₅, R₄ is hydroxy, and R₅ is hydrogen, then R₆ is other than hydrogen; and

when R₂ is trifluoromethyl, R₃ is selected from the group consisting of —CO₂H and —CO₂C₂H₅, R₅ is methyl, and R₆ is selected from the group consisting of hydrogen and trifluoromethyl, then R₄ is other than hydroxy.

Among the objects of the present method are the inhibition of CTEP in vivo; the treatment or prevention of coronary artery disease; the treatment or prevention of atherosclerosis; the alteration of the LDL/HDL ratio or profile in plasma; and the elevation of HDL levels in plasma.

The present invention is additionally directed to the novel substituted pyridines of Formula IIA:

wherein:

R₂ and R₆ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R₂ and R₆ is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;

R₃ is selected from the group consisting of arylcarbonyl, heteroarylcarbonyl, hydroxymethyl, arylalkoxyalkyl, trialkylsilyloxyalkyl,

—CHO,

—CO₂R₇,

wherein R₇ is selected from the group consisting of hydrogen and alkyl; and

wherein R_(15a) is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, and

R_(16a) is selected from the group consisting of alkyl, haloalkyl, alkenyl, aryl and heteroaryl;

R₄ is selected from the group consisting of hydrogen, hydroxy, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, alkoxy, thio, trialkylsilyl, alkylamino, and —OC(O)N(R₈)₂, wherein R₈ is aryl;

R₅ is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aralkyl, alkoxy, aryloxy, cycloalkylthioalkyl, arylthioalkyl, heteroarylthioalkyl, alkoxyalkenyl, arylcarbonyloxyalkyl, pyrrolyl, substituted pyrrolidinyl, hydroxymethyl, arylalkoxyalkyl, and trialkylsilyloxyalkyl,

—CO₂R₁₄,

wherein R₁₄ is alkyl;

wherein R_(15b) is selected from the group consisting of hydroxy, halogen, alkoxy, and alkylthio, aroyloxy, and alkylsulfonyloxy, and

R_(16b) is selected from the group consisting of alkyl, alkenyl, aryl, and heteroaryl;

wherein R₁₇ and R₁₈ are independently alkyl;

wherein R₁₉ is aryl, heteroaryl, —SR₂₀, and —OR₂₁,

wherein R₂₀ is selected from the group consisting of aryl, heteroaryl and aminoalkyl, and

R₂₁ is selected from the group consisting of aryl and heteroaryl;

wherein R₂₄ is aralkyl;

wherein R₂₈ and R₂₉ are independently alkyl;

wherein R₃₀ and R₃₁ are independently alkoxy;

—C≡C—Si(R₃₆)₃,

wherein R₃₆ is alkyl;

wherein R₃₇ is selected from the group consisting of hydrogen, alkoxy, and alkylthio, and

R₃₈ is selected from the group consisting of haloalkyl, cycloalkyl, heterocyclylalkoxy, and alkylthio;

provided that when R₃₇ is hydrogen, then R₃₈ is selected from the group consisting of haloalkyl, cycloalkyl, and heterocyclylalkoxy;

wherein R₄₂ is selected from the group consisting of hydrogen and alkyl, and

R₄₃ is substituted heteroaryl;

wherein R₄₄ is selected from the group consisting of aryl and heteroaryl;

—SR₄₅,

wherein R₄₅ is selected from the group consisting of haloalkyl, heterocyclyl, alkylthioalkyl, aminocarbonylalkyl, —SR₄₆, and —CH₂R₄₇,

wherein R₄₆ is selected from the group consisting of aryl and heteroaryl, and

R₄₇ is selected from the group consisting of methylenedioxyphenyl, pyridyl, quinolinyl, tetrahydronaphthyl and benzodioxanyl;

wherein R₄₈ is selected from the group consisting of hydrogen and alkyl, and

R₄₉ is selected from the group consisting of alkoxy and haloalkyl;

wherein R₅₀ is selected from the group consisting of alkyl, alkoxy, and heteroaryl; and

wherein R₅₁ is haloalkyl;

or a pharmaceutically acceptable salt or tautomer thereof,

provided that:

when R₂ is selected from the group consisting of difluoromethyl and trifluoromethyl, R₃ is selected from the group consisting of —CO₂H, —CO₂CH₃ and —CO₂C₂H₅, R₅ is hydrogen, and R₆ is selected from the group consisting of hydrogen and trifluoromethyl, then R₄ is other than hydrogen, hydroxy or iso-butyl; provided further that when R₂, R₃ and R₅ are as defined above, and R₄ is selected from the group consisting of alkylamino and alkoxy, then R₆ is hydrogen;

when R₂ is selected from the group consisting of fluorinated methyl and chlorofluorinated methyl, R₃ is selected from the group consisting of hydroxymethyl and CO₂R₇, R₅ is selected from the group consisting of hydroxymethyl and CO₂R₁₄, R₆ is selected from the group consisting of alkyl, fluorinated methyl and chlorofluorinated methyl, and R₇ and R₁₄ are independently alkyl, then R₄ is other than alkyl, cycloalkyl, cycloalkylalkyl, hydroxy, alkoxy, aryl, alkylamino and heteroarylalkyl;

when R₂ is selected from the group consisting of difluoromethyl and trifluoromethyl, R₃ is —CO₂C₂H₅, R₄ is hydrogen, and R₅ is —CO₂C₂H₅, then R₆ is other than trifluoromethyl;

when R₂ is trifluoromethyl, R₃ is CO₂R₇, R₅ is methyl, and R₆ is selected from the group consisting of fluorinated methyl, fluorinated ethyl and chlorofluorinated methyl, then R₄ is other than alkoxy, alkylamino and hydroxy;

when R₄ is selected from the group consisting of alkyl, cycloalkyl and cycloalkylalkyl, R₃ is —CO₂R₇, and R₇ is alkyl, then R₅ is other than arylcarbonyl, heteroarylcarbonyl or

wherein R_(16b) is alkyl when R_(15b) is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, or wherein R_(16b) is aryl or heteroaryl when R_(15b) is hydroxy;

when R₄ is selected from the group consisting of alkyl, cycloalkyl and cycloalkylalkyl, R₅ is —CO₂R₁₄, and R₁₄ is alkyl, then R₃ is other than arylcarbonyl, heteroarylcarbonyl or

wherein R_(16a) is alkyl when R_(15a) is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, or wherein R_(16a) is aryl or heteroaryl when R_(15a) is hydroxy; and

when R₂ and R₆ are independently selected from fluorinated methyl and chlorofluorinated methyl, R₃ is CO₂R₇, R₅ is hydroxy, alkoxy or aryloxy, then R₄ is other than hydrogen, hydroxy, alkyl or alkoxy; and

when R₄ is aryl and one of R₂ and R₆ is trifluoromethyl, then the other of R₂ and R₆ is difluoromethyl.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Novel Methods

The present invention comprises a method for the treatment or prophylaxis of CTEP-mediated disorders (such as coronary artery disease) in a subject, comprising administering to the subject having such a disorder a therapeutically-effective amount of a compound of Formula I:

wherein:

R₂ and R₆ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R₂ and R₆ is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;

R₃ is selected from the group consisting of hydroxy, amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl,

—CHO,

—CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen, alkyl and cyanoalkyl; and

wherein R_(15a) is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy, and

R_(16a) is selected from the group consisting of alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, and heterocyclyl, arylalkoxy, trialkylsilyloxy;

R₄ is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloyloxy, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, heterocyclylamino, aryldialkylamino, diarylamino, diheteroarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, trialkylsilyl, trialkenylsilyl, triarylsilyl,

—OC(O)N(R_(8a)R_(8b)), wherein R_(8a) and R_(8b) are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,

—SO₂R₉, wherein R₉ is selected from the group consisting of hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,

—OP(O) (OR_(10a)) (OR_(10b)), wherein R_(10a) and R_(10b) are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and

—OP(S) (OR_(11a)) (OR_(11b)), wherein R_(11a) and R_(11b) are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

R₅ is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl, arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl, heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkenyl, alkenoxyalkenyl, alkynoxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl, heterocyclyloxyalkenyl, cyano, hydroxymethyl,

—CO₂R₁₄,

wherein R₁₄ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

wherein R_(15b) is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy, and

R_(16b) is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, and trialkylsilyloxy;

wherein R₁₇ and R₁₈ are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

wherein R₁₉ is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —SR₂₀, —OR₂₁, and —R₂₂CO₂R₂₃, wherein

R₂₀ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocyclyl, alkylheteroarylamino, arylheteroarylamino,

R₂₁ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl,

R₂₂ is selected from the group consisting of alkylene or arylene, and

R₂₃ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R₂₄ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, aralkenyl, and aralkynyl;

wherein R₂₅ is heterocyclylidenyl;

wherein R₂₆ and R₂₇ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R₂₈ and R₂₉ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R₃₀ and R₃₁ are independently alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy; and

wherein R₃₂ and R₃₃ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

 —C≡C—Si(R₃₆)₃,

wherein R₃₆ is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl and heterocyclyl;

wherein R₃₇ and R₃₈ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R₃₉ is selected from the group consisting of hydrogen, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio, and

R₄₀ is selected from the group consisting of haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy, heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio;

—N═R₄₁,

wherein R₄₁ is heterocyclylidenyl;

wherein R₄₂ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, and

R₄₃ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, and haloheterocyclyl;

wherein R₄₄ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

—N═S═O;

—N═C═S;

—N═C═O;

—N₃;

—SR₄₅,

wherein R₄₅ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl, aminocarbonylaryl, aminocarbonylheteroaryl, and aminocarbonylheterocyclyl, —SR₄₆, and —CH₂R₄₇,

wherein R₄₆ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and

R₄₇ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; and

wherein R₄₈ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and

R₄₉ is selected from the group consisting of alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;

wherein R₅₀ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy;

wherein R₅₁ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl; and

wherein R₅₃ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

or a pharmaceutically acceptable salt or tautomer thereof,

provided that when R₅ is selected from the group consisting of heterocyclylalkyl and heterocyclylalkenyl, then the heterocyclyl radical of the corresponding heterocyclylalkyl or heterocyclylalkenyl is other than a δ-lactone; and

provided that when R₄ is aryl, heteroaryl or heterocyclyl, and one of R₂ and R₆ is trifluoromethyl, then the other of R₂ and R₆ is difluoromethyl.

In another embodiment, the method comprises the administration of a therapeutically effective amount of a substituted pyridine of Formula IA:

wherein:

R₂ and R₆ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R₂ and R₆ is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;

R₃ is selected from the group consisting of hydroxy, amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl,

—CO₂R₇,

wherein R₇ is selected from the group consisting of hydrogen, alkyl (preferably methyl or ethyl) and cyanoalkyl; and

wherein R_(15a) is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, and

R_(16a) is selected from the group consisting of alkyl, aryl and heteroaryl;

R₄ is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, aralkoxy, alkoxycarbonyl, arylcarbonyloxy, thio, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, alkylamino, trialkylsilyl,

—OC(O)N(R₈)₂, wherein R₈ is aryl,

—SO₂R₉, wherein R₉ is aryl,

—OP(O) (OR₁₀)₂, wherein R₁₀ is alkyl, and

—OP(S) (OR₁₁)₂, wherein R₁₁ is alkyl;

R₅ is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, haloalkyl, alkynyl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylcarbonyloxyalkyl, heterocyclylalkyl, alkylthioalkyl, arylthioalkyl, heteroarylthioalkyl, alkoxyalkenyl, cyano, hydroxymethyl,

—CO₂R₁₄,

wherein R₁₄ is alkyl;

wherein R_(15b) is selected from the group consisting of hydroxy, hydrogen, alkylthio and alkoxy, and

R_(16b) is selected from the group consisting of alkyl, aryl and heteroaryl;

wherein R₁₇ and R₁₈ are independently alkyl;

wherein R₁₉ is selected from the group consisting of aryl, heteroaryl, —SR₂₀, —OR₂₁, and —R₂₂CO₂R₂₃,

wherein R₂₀ is selected from the group consisting of alkyl, aryl and aminoalkyl,

R₂₁ is aryl,

R₂₂ is alkylene, and

R₂₃ is alkyl;

wherein R₂₄ is selected from the group consisting of hydrogen, unsubstituted alkyl, and aralkyl;

wherein R₂₅ is heterocyclylidenyl;

wherein R₂₆ and R₂₇ are independently alkyl;

wherein R₂₈ and R₂₉ are independently alkyl;

wherein R₃₀ and R₃₁ are independently alkoxy;

wherein R₃₂ is selected from the group consisting of hydrogen and alkyl, and

R₃₃ is alkyl;

 —C≡C—Si(R₃₆)₃,

wherein R₃₆ is alkyl;

wherein R₃₇ and R₃₈ are independently alkyl;

wherein R₃₉ is selected from the group consisting of hydrogen, alkoxy, and alkylthio, and

R₄₀ is selected from the group consisting of haloalkyl, cycloalkyl, heterocyclylalkoxy, and alkylthio;

—N═R₄₁, wherein R₄₁ is heterocyclylidenyl;

wherein R₄₂ is selected from the group consisting of hydrogen and alkyl, and

R₄₃ is selected from the group consisting of cycloalkyl, chlorinated alkyl and substituted heteroaryl;

wherein R₄₄ is heteroaryl;

—N═S═O;

—N═C=S;

—N═C═O;

—N₃;

 —SR₄₅,

wherein R₄₅ is selected from the group consisting of hydrogen, alkyl, haloalkyl, heterocyclyl, aralkyl, heteroaralkyl, alkylthioalkyl, aminocarbonylalkyl, —SR₄₆, and —CH₂R₄₇,

wherein R₄₆ is selected from the group consisting of aryl and heteroaryl, and

R₄₇ is selected from the group consisting of aryl and heteroaryl; and

wherein R₄₈ is selected from the group consisting of hydrogen and alkyl, and

R₄₉ is selected from the group consisting of alkoxy and haloalkyl;

wherein R₅₀ is selected from the group consisting of alkyl, alkoxy, aryl and heteroaryl;

wherein R₅₁ is selected from the group consisting of haloalkyl and alkyl; and

wherein R₅₃ is aryl;

or a pharmaceutically acceptable salt or tautomer thereof,

provided that when R₅ is selected from the group consisting of heterocyclylalkyl and heterocyclylalkenyl, then the heterocyclyl radical is other than a δ-lactone and the alkyl or alkenyl radical is other than —CH₂CH₂— or —CH═CH—.

Preferably, the immediately preceding embodiment involves the administration of a substituted pyridine of Formula IA as described above wherein:

when R₂ is difluoromethyl, R₃ is —CO₂CH₃, R₅ is

R₆ is trifluoromethyl, and R₁₉ is the heteroaryl 1-pyrazolyl, then R₄ is selected from the group consisting of hydrogen, hydroxy, halogen, alkoxy, cycloalkyl, haloalkyl, alkenyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, aralkoxy, alkoxycarbonyl, arylcarbonyloxy, thio, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, trialkylsilyl,

—OC(O)N(R₈)₂, wherein R₈ is aryl,

—SO₂R₉, wherein R₉ is aryl,

—OP(O) (OR₁₀)₂, wherein R₁₀ is alkyl, and

—OP(S) (OR₁₁)₂, wherein R₁₁ is alkyl; and

when R₂ is difluoromethyl, R₃ is —CO₂CH₃, R₅ is the heterocyclyl 2-(4,5-dihydro-oxazolyl), and R₆ is trifluoromethyl, then R₄ is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heteroaryl, heteroarylalkyl, aralkenyl, alkoxy, aralkoxy, alkoxycarbonyl, arylcarbonyloxy, thio, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, alkylamino, trialkylsilyl,

—OC(O)N(R₈)₂, wherein R₈ is aryl,

—SO₂R₉, wherein R₉ is aryl,

—OP(O) (OR₁₀)₂, wherein R₁₀ is alkyl, and

—OP(S) (OR₁₁)₂, wherein R₁₁ is alkyl; and

when R₂ and R₆ are independently fluorinated methyl, R₃ is —CO₂R₇, R₅ is cyano, and R₇ is selected from the group consisting of hydrogen and alkyl, then R₄ is selected from the group consisting of hydrogen, hydroxy, halogen, cycloalkyl, haloalkyl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, aralkoxy, alkoxycarbonyl, arylcarbonyloxy, thio, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, alkylamino, trialkylsilyl,

—OC(O)N(R₈)₂, wherein R₈ is aryl,

—SO₂R₉, wherein R₉ is aryl,

—OP(O) (OR₁₀)₂, wherein R₁₀ is alkyl, and

—OP(S) (OR₁₁)₂, wherein R₁₁ is alkyl; and

when R₂ is methyl, R₃ is —CO₂C₂H₅, R₅ is

R₆ is methyl, and R₂₄ is aralkyl, then R₄ is selected from the group consisting of hydroxy, halogen, alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, aralkoxy, alkoxycarbonyl, arylcarbonyloxy, thio, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, alkylamino, trialkylsilyl,

—OC(O)N(R₈)₂, wherein R₈ is aryl,

—SO₂R₉, wherein R₉ is aryl,

—OP(O) (OR₁₀)₂, wherein R₁₀ is alkyl, and

—OP(S) (OR₁₁)₂, wherein R₁₁ is alkyl, and

when R₂ is methyl, R₃ and R₅ are —CO₂C₂H₅, and R₄ is alkoxy, then R₆ is selected from the group consisting of hydrogen, hydroxy, alkyl comprising at least two carbon atoms, fluorinated alkyl, chlorofluorinated alkyl, alkoxy, alkoxyalkyl, and alkoxycarbonyl,

when R₂ is difluoromethyl, R₃ is —CO₂R₇, R₄ is alkenyl, R₅ is CO₂CH₃, and R₆ is trifluoromethyl, then R₇ is selected from the group consisting of alkyl and cyanoalkyl,

when R₂ is methyl, R₄ is hydrogen, R₅ is CO₂C₂H₅, and R₆ is methyl, then R₃ is selected from the group consisting of hydroxy, amido and —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen, methyl, alkyl comprising at least three carbon atoms, and cyanoalkyl,

when R₂ is difluoromethyl, R₄ is hydrogen, R₅ is CO₂C₂H₅, and R₆ is trifluoromethyl, then R₃ is selected from the group consisting of hydroxy, amido and —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen, methyl, alkyl comprising at least three carbon atoms, and cyanoalkyl,

when R₂ is difluoromethyl, R₄ is alkylthioalkyl, R₅ is —CO₂C₂H₅, and R₆ is trifluoromethyl, then R₃ is selected from the group consisting of hydroxy, amido and —CO₂R₇, wherein R₇ is selected from the group consisting of alkyl and cyanoalkyl,

when R₂ is trifluoromethyl, R₃ is —CO₂CH₃, R₄ is alkyl, R₅ is —CO₂CH₃, then R₆ is selected from the group consisting of hydrogen, hydroxy, alkyl comprising at least two carbon atoms, fluorinated alkyl, chlorofluorinated alkyl, alkoxy, alkoxyalkyl, and alkoxycarbonyl,

when R₂ is difluoromethyl, R₄ is alkyl, R₅ is —CO₂R₁₄, R₆ is trifluoromethyl, and R₁₄ is alkyl, then R₃ is selected from the group consisting of hydroxy and —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen, alkyl and cyanoalkyl,

when R₂ is selected from the group consisting of hydroxy and trifluoromethyl, R₄ and R₅ are hydrogen, and R₆ is selected from the group consisting of methyl and trifluoromethyl, then R₃ is selected from the group consisting of hydroxy, amido and —CO₂R₇, wherein R₇ is selected from the group consisting of alkyl and cyanoalkyl,

when R₂ is selected from the group consisting of methyl, difluoromethyl and trifluoromethyl, R₃ is —CO₂CH₃, R₅ is hydrogen, and R₆ is selected from the group consisting of methyl and trifluoromethyl, then R₄ is selected from the group consisting of hydrogen, hydroxy, halogen, cycloalkyl, alkenyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, aralkoxy, alkoxycarbonyl, thio, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, alkylamino, trialkylsilyl,

—OC(O) N(R₈)₂, wherein R₈ is aryl,

—SO₂R₉, wherein R₉ is aryl,

—OP(O) (OR₁₀)₂, wherein R₁₀ is alkyl; and

—OP(S) (OR₁₁)₂, wherein R₁₁ is alkyl; and

when R₂ is trifluoromethyl, R₃ is —CO₂C₂H₅, R₄ is hydroxy, and R₅ is hydrogen, then R₆ is selected from the group consisting of hydroxy, alkyl, fluorinated alkyl, alkoxy, alkoxyalkyl and alkoxycarbonyl; and

when R₂ is trifluoromethyl, R₃ is selected from the group consisting of —CO₂H and —CO₂C₂H₅, R₅ is methyl, and R₆ is selected from the group consisting of hydrogen and trifluoromethyl, then R₄ is selected from the group consisting of hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heteroaryl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, aralkoxy, alkoxycarbonyl, arylcarbonyloxy, thio, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, alkylamino, trialkylsilyl,

—OC(O)N(R₈)₂, wherein R₈ is aryl,

—SO₂R₉, wherein R₉ is aryl,

—OP(O) (OR₁₀)₂, wherein R₁₀ is alkyl, and

—OP(S) (OR₁₁)₂, wherein R₁₁ is alkyl.

In another embodiment, the method comprises the administration of a therapeutically effective amount of a substituted pyridine of Formula IA as defined in one of the embodiments discussed above wherein:

R₂ is selected from the group consisting of methyl and fluorinated methyl; and

R₃ is —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen, methyl and ethyl.

Pharmaceutically Acceptable Salts

Also included in the family of compounds of Formulae I, IA and IB used in the method of the present invention (as well as in the family of novel compounds of Formula IIA and IIB discussed below) are the pharmaceutically-acceptable salts thereof. The term “pharmaceutically-acceptable salts” embraces salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically acceptable. Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucoronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethylsulfonic, benzenesulfonic, sulfanilic, stearic, cyclohexylaminosulfonic, algenic, galacturonic acid. Suitable pharmaceutically-acceptable base addition salts include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from N,N′-dibenzylethylenediamine, choline, chloroprocaine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procain. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.

Treatment of CETP-Mediated Disorders

The methods of this invention additionally can be used, for example: (i) to inhibit cholesteryl ester transfer protein (CETP) activity, (ii) to decrease the concentrations of low density lipoprotein (LDL) and/or raise the level of high density lipoprotein (HDL), or otherwise alter lipoprotein profiles, resulting in a therapeutically beneficial plasma lipid profile; (iii) for the primary and secondary treatment of coronary artery disease, myocardial infarction and agina; (iv) for the treatment of dyslipidemia (hypoalphalipoproteinaemia), hyperlipoproteinaemia (chylomicronemia and hyperapobetalipoproteinaemia), peripheral vascular disease, hypercholesterolemia, atherosclerosis, and other CETP-mediated disorders; (v) for the prophylactic treatment of subjects who are at risk of developing CETP-mediated disorders; and (vi) to lower the risk of atherosclerosis. The methods would be also useful in prevention of cerebral vascular accident (CVA) or stroke.

Besides being useful for human treatment, these methods are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats.

Without being limited to a specific theory, applicant hypothesizes that the CETP molecule contains one or more specific hydrophobic binding sites that can accommodate the substituted pyridines of the present invention. Binding of the substituted pyridine to these sites is sufficient to inhibit CETP. This binding is generally rapid and reversible.

It is additionally hypothesized that the CETP molecule contains a cysteine at or near these hydrophobic binding sites. Inhibition potency can be enhanced by selecting a substituted pyridine which is capable of undergoing a disulfide exchange with this cysteine. This disulfide exchange is time-dependent and irreversible. While inhibition potency may be enhanced as a result of this disulfide exchange, substituted pyridines which are effective inhibitors and which do not undergo the disulfide exchange may be more desirable given the generally irreversible nature of the disulfide exchange reaction.

It is further hypothesized that such disulfide-modified CETP molecules can aggregate, perhaps as a result of conformational changes induced by interaction with the substituted pyridine.

Additional Embodiments of Novel Methods

In another embodiment, the method comprises the administration of a therapeutically effective amount of a compound of Formula IA wherein:

R₂ is fluorinated alkyl;

R₃ is —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen and alkyl;

R₄ is selected from the group consisting of alkyl, cycloalkyl and cycloalkylalkyl;

R₅ is selected from the group consisting of:

heteroaryl (preferably 1-pyrrolyl);

wherein R₃₇ and R₃₈ are independently alkyl;

wherein R₃₉ is selected from the group consisting of hydrogen, alkoxy, and alkylthio, and

R₄₀ is selected from the group consisting of haloalkyl, cycloalkyl, heterocyclylalkoxy, and alkylthio;

—N═R₄₁,

wherein R₄₁ is heterocyclylidenyl;

wherein R₄₂ is selected from the group consisting of hydrogen and alkyl, and

R₄₃ is selected from the group consisting of cycloalkyl, chlorinated alkyl, and heteroaryl;

wherein R₄₄ is heteroaryl (preferably substituted pyridyl);

—N═S═O;

—N═C═S;

—N═C═O; and

—N₃; and

R₆ is fluorinated alkyl;

or a pharmaceutically acceptable salt or tautomer thereof.

In still another embodiment, the method comprises the administration of a therapeutically effective amount of a compound of Formula IA wherein:

R₂ is fluorinated alkyl;

R₃ is —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen and alkyl;

R₄ is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, alkoxy and alkylthio;

R₅ is selected from the group consisting of:

—SR₄₅,

wherein R₄₅ is selected from the group consisting of hydrogen, alkyl, haloalkyl, heterocyclyl, aralkyl, heteroaralkyl, aminocarbonylalkyl, alkylthioalkyl, —SR₄₆, and —CH₂R₄₇,

wherein R₄₆ is selected from the group consisting of aryl (preferably substituted aryl) and heteroaryl (preferably substituted pyridyl), and

R₄₇ is selected from the group consisting of aryl and heteroaryl (R₄1 is preferably substituted aryl); and

wherein R₄₈ is selected from the group consisting of hydrogen and alkyl, and

R₄₉ is selected from the group consisting of alkoxy and haloalkyl;

wherein R₅₀ is selected from the group consisting of alkyl, alkoxy, aryl and heteroaryl (preferably substituted heteroaryl);

wherein R₅₁ is selected from the group consisting of alkyl and haloalkyl; and

wherein R₅₃ is aryl; and

R₆ is fluorinated alkyl;

or a pharmaceutically acceptable salt or tautomer thereof.

In still another embodiment, the method comprises the administration of a therapeutically effective amount of a compound of Formula IA wherein:

R₂ is selected from the group consisting of alkyl and fluorinated alkyl;

R₃ is —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen and alkyl;

R₄ is selected from the group consisting of hydroxy, alkoxy, aralkoxy, alkoxycarbonyl, alkylthio, arylthio,

—OC(O)N(R₈)₂, wherein R₈ is aryl,

—SO₂R₉, wherein R₉ is aryl,

—OP(O) (OR₁₀)₂, wherein R₁₀ is alkyl, and

—OP(S) (OR₁₁)₂, wherein R₁₁ is alkyl;

R₅ is selected from the group consisting of hydrogen, hydroxy, halogen, alkoxy, and aryloxy; and

R₆ is selected from the group consisting of hydrogen, fluorinated alkyl and alkoxycarbonyl;

or a pharmaceutically acceptable salt or tautomer thereof,

provided that when R₂ is trifluoromethyl, R₃ is —CO₂C₂H₅, R₄ is hydroxy and R₅ is hydrogen, then R₆ is selected from the group consisting of fluorinated alkyl and alkoxycarbonyl.

In yet another preferred embodiment, the method comprises the administration of a therapeutically effective amount of a compound of Formula IA wherein:

R₂ is fluorinated alkyl;

R₃ is —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen, alkyl and cyanoalkyl;

R₄ is selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, arylcarbonyloxy, arylthio, and alkylamino;

R₅ is selected from the group consisting of alkyl, haloalkyl, alkynyl, heterocyclyl, heteroaryl, heterocyclylalkyl, arylcarbonyloxyalkyl, alkylthioalkyl, arylthioalkyl, heteroarylthioalkyl, alkoxyalkenyl, cyano,

wherein R_(15a) is selected from the group consisting of hydroxy, alkylthio and alkoxy, and

R_(16b) is selected from the group consisting of alkyl and heteroaryl;

wherein R₁₇ and R₁₈ are each alkyl;

wherein R₁₉ is selected from the group consisting of heteroaryl (preferably a substituted pyridyl), —SR₂₀, —OR₂₁, and —R₂₂CO₂R₂₃,

wherein R₂₀ is selected from the group consisting of alkyl, aryl (preferably substituted aryl) and aminoalkyl,

R₂₁ is aryl (preferably substituted aryl),

R₂₂ is alkylene, and

R₂₃ is alkyl;

wherein R₂₄ is selected from the group consisting of hydrogen, unsubstituted alkyl, and aralkyl;

wherein R₂₅ is heterocyclylidenyl;

wherein R₂₆ and R₂₇ are independently alkyl;

wherein R₂₈ and R₂₉ are independently alkyl;

wherein R₃₀ and R₃₁ are each alkoxy;

wherein R₃₂ is selected from the group consisting of hydrogen and alkyl, and R₃₃ is alkyl;

 —C≡C—Si(R₃₆)₃,

wherein R₃₆ is alkyl; and

R₆ is selected from the group consisting of hydrogen, fluorinated alkyl and alkoxy,

or a pharmaceutically acceptable salt or tautomer thereof,

provided that:

when R₂ is difluoromethyl, R₃ is —CO₂CH₃, R₅ is

R₆ is trifluoromethyl, and R₁₉ is the heteroaryl 1-pyrazolyl, then R₄ is selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, arylcarbonyloxy, and arylthio; and

when R₂ is difluoromethyl, R₃ is —CO₂CH₃, R₅ is the heterocyclyl 2-(4,5-dihydro-oxazolyl), and R₆ is trifluoromethyl, then R₄ is selected from the group consisting of alkyl, alkoxy, cycloalkyl, arylcarbonyloxy, arylthio, and alkylamino; and

when R₂ and R₆ are independently fluorinated methyl, R₃ is —CO₂R₇, R₅ is cyano, and R₇ is selected from the group consisting of hydrogen and alkyl, then R₄ is selected from the group consisting of alkoxy, cycloalkyl, cycloalkylalkyl, arylcarbonyloxy, arylthio, and alkylamino.

In yet another embodiment, the method comprises the administration of a therapeutically effective amount of a compound of Formula IA wherein:

R₂ is selected from the group consisting of hydroxy, alkyl, fluorinated alkyl, and alkoxyalkyl;

R₃ is selected from the group consisting of hydroxy, amido, and —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen and alkyl;

R₄ is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heteroaryl, heteroarylalkyl, alkoxy, alkoxycarbonyl, aralkenyl, thio, alkylthio, cycloalkylthio, heterocyclylthio, alkylthioalkyl, and trialkylsilyl;

R₅ is CO₂R₁₄, wherein R₁₄ is alkyl;

R₆ is selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, and alkoxyalkyl;

or a pharmaceutically acceptable salt or tautomer thereof,

provided that:

when R₂ is methyl, R₃ is —CO₂C₂H₅, R₄ is alkoxy, and R₅ is —CO₂C₂H₅, then R₆ is selected from the group consisting of hydrogen, hydroxy, alkyl comprising at least two carbon atoms, fluorinated alkyl, and alkoxyalkyl;

when R₂ is difluoromethyl, R₃ is —CO₂R₇, R₄ is alkenyl, R₅ is CO₂CH₃, and R₆ is trifluoromethyl, then R₇ is alkyl;

when R₂ is methyl, R₄ is hydrogen, R₅ is CO₂R₁₄, R₆ is methyl, and R₁₄ is alkyl, then R₃ is selected from the group consisting of hydroxy, amido and —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen, methyl, alkyl comprising at least three carbon atoms and cyanoalkyl;

when R₂ is difluoromethyl, R₄ is hydrogen, R₅ is CO₂R₁₄, R₆ is trifluoromethyl, and R₁₄ is alkyl, then R₃ is selected from the group consisting of hydroxy, amido and —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen, methyl, alkyl comprising at least three carbon atoms and cyanoalkyl;

when R₂ is difluoromethyl, R₄ is alkylthioalkyl, R₅ is CO₂C₂H₅, and R₆ is methyl, then R₃ is selected from the group consisting of hydroxy, amido and —CO₂R₇, wherein R₇ is alkyl;

when R₂ is trifluoromethyl, R₃ is —CO₂CH₃, R₄ is alkyl, and R₅ is —CO₂CH₃, then R₆ is selected from the group consisting of hydrogen, hydroxy, alkyl comprising two or more carbon atoms, fluorinated alkyl, and alkoxyalkyl; and

when R₂ is difluoromethyl, R₄ is alkyl, R₅ is yselected from the group consisting of —CO₂CH₃ and —CO₂C₂H₅, and R₆ is trifluoromethyl, then R₃ is selected from the group consisting of hydroxy and —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen and alkyl.

In yet another embodiment, the method comprises the administration of a therapeutically effective amount of a compound of Formula IA which is selected from the compounds disclosed in Tables 1-8 below. While a number of the compounds disclosed in Tables 1-7 below either were specifically known or generically disclosed in the art as herbicides, they were not known to possess the pharmacologic properties of the present invention. Among the compounds of Tables 1-7 used in the method which were not previously specifically known or generically disclosed in the art as herbicides are those compounds identified with an asterisk.

TABLE 1 (T-1)

Procedure Compound R₂ R₃ R₄ R₅ R₆ Reference IC₅₀(μm)  1 CF₂H CO₂CH₃ i-Bu N═S═O CF₃ U.S. Pat. No. 4,885,026 2 EXAMPLE 165  2* CF₂H CO₂CH₃ SH CO₂C₂H₅ CF₃ EXAMPLE 2^(A) 3  3* CF₂H CO₂CH₃ i-Bu CH₂S-(4-t- CF₃ EXAMPLE 3^(A) 9 butylphenyl)  4* CF₂H CO₂CH₃ S-(4,5- CO₂C₂H₅ CF₃ U.S. Pat. No. 4,698,093 6 dihydro -2- EXAMPLE 169 thiazolyl)  5* CF₂H CO₂CH₃ i-Bu SC(O)C₁₅H₃₁ CF₃ EXAMPLE 23^(A) 8  6 CF₂H CO₂CH₃ i-Bu SCO₂CH₃ CF₃ EXAMPLE 11^(A) 8  7 CF₂H CO₂CH₃ i-Bu SH CF₃ EXAMPLE 1^(A) 8.75  8 CF₂H CO₂CH₃ i-Bu (1,4-dithian-2- CF₃ U.S. Pat. No. 5,129,943 10 ylidene) amino EXAMPLE43  9 CF₂H CO₂-t- i-Bu CO₂-t-Bu CF₃ EXAMPLE 9^(A) 20 Bu 10 CF₃ CO₂C₂H₅ OC(0)[4- CH₃ CF₃ U.S. Pat. No. 4,655,816 25 trifluoro EXAMPLE 61 methyl)- phenyl] 11 CF₃ CO₂C₂H₅ S-(4-i- CH₃ CF₃ EXAMPLE 4^(A) 25 propylphenyl) 12 CF₃ CO₂CH₃ i-Bu 4,5-dihydro-2- CF₃ U.S. Pat. No. 4,988,384 25 thiazolyl EXAMPLE 21 13 CF₂H CO₂CH₃ i-Bu CH(OH)-2-furyl CF₃ U.S. Pat. No. 3,280,262 30 EXAMPLE H 14 CF₂H CO₂CH₃ c-Bu C(O)S-i-Pr CF₃ EXAMPLE 12^(A) 30 15 CF₂H CO₂C₂H₅ i-Bu (tran-4,5-di- CF₃ U.S. Pat. No. 5,125,961 30 chloro-4,5- dihydro-3 isoxazolyl EX.37, CMPD. 24 16* CF₂H CO₂CH₃ i-Bu N═C(OCH₃)CH₂Br CF₃ U.S. Pat. No. 4,885,026 30 SEE EX. 131 17 CF₃H CO₂CH₃ i-Bu 4,5-dihydro-4- CF₃ U.S. Pat. No. 4,988,384 30 ethylidine-5- oxo-2-oxazolyl EXAMPLE 73 18 CF₂H CO₂CH₃ i-Bu N═C═S CF₃ U.S. Pat. No. 5,129,943 35 EX. 41, STEP A 19* CF₂H CO₂CH₃ i-Bu C≡CSi(CH₃)₃ CF₃ EXAMPLE 21^(A) 35 20 CH₃ CO₂C₂H₅ i-Bu CO₂C₂H₅ CF₃ U.S. Pat. No. 4,692,184 37.5 EXAMPLE 246 21 CF₂H CO₂CH₃ CH₂c-Pr CH(CH₃)SC₂H₅ CF₃ U.S. Pat. No. 5,169,432 40 EXAMPLE 56 22 CF₂H CO₂C₂H₅ S-c-C₅H₉ CO₂C₂H₅ CF₃ U.S. Pat. No. 4,698,093 40 EXAMPLE 109 23 CF₃ CO₂C₂H₅ S—Ph H CF₃ U.S. Pat. No. 4,655,816 40 EXAMPLE 23 24 CF₃ CO₂CH₃ OP(S)(OCH₃)₂ H CF₃ U.S. Pat. No. 4,655,816 40 EXAMPLE 93 25* CF₃ CO₂CH₃ OC(O)NPh₂ H CF₃ EXAMPLE 13^(A) 40 26 CF₂H CO3CH₃ i-Bu CH₂SC₂H₃ CF₃ U.S. Pat. No. 5,169,432 40 EXAMPLE 47 27* CF₂H CO₂CH₃ i-Bu N═C(OCH₃)SCH₃ CF₃ EXAMPLE 34^(A) 40 28 CF₂H CO₂CH₃ i-Bu C≡CH CF₃ U.S. Pat. No. 5,125,961 40 EXAMPLE 117 29* CF₂H CO₂CH₃ i-Bu N═C(OCH₃)c-Pr CF₃ U.S. Pat. No. 4,885,026 40 SEE EX. 131 30* CF₂H CO₂CH₃ i-Bu N═CHOCH₂-(2- CF₃ EXAMPLE 36^(A) 40 oxiranyl) 31* CF₃ CO₂C₂H₅ Si(CH₃)₃ CO₂C₂H₅ CF₃ EXAMPLE 26^(A) 40 32 CF₂H CO₂CH₃ i-Bu CH₃I CF₃ EXAMPLE 37^(A) 45 33* CF₂H CO₂CH₃ i-Bu SCH₂SCH₃ CF₃ SEE EX. 23^(A) 45 34* CF₂H CO₂CH₃ i-Bu CH(OCH₃)-(5- CF₃ EXAMPLE 38^(A) 45 isothiazolyl) 35* CF₂H CO₂CH₃ CH₃-c-Pr C(Br)═CHOCH₃ CF₃ EXAMPLE 52^(A) 45 36 CF₃ CO₂C₂H₅ i-Bu CO₂C₂H₅ CF₃ U.S. Pat. No. 4,692,184 45 EXAMPLE 7 37 CF₃ CO₂C₂H₅ OCH₂Ph H CF₃ U.S. Pat. No. 4,655,816 45 EXAMPLE 9 38 CF₂H CO₂C₂H₅ c-Hx CO₂C₂H₅ CF₃ U.S. Pat. No. 4,692,184 50 EXAMPLE 21 39 CF₂H CO₂C₂H₅ S-t-Bu CO₂C₂H₅ CF₃ U.S. Pat. No. 4,698,093 50 EXAMPLE 108 40* CF₂H CO₂CH₃ i-Bu CH(OCH₃)-(2- CF₃ SEE EX. 38^(A) 50 thienyl) 41* CF₂H CO₂CH₃ CH₂-c-Pr CH₂OC(O)Ph CF₃ EXAMPLE 39^(A) 50 42* CF₂H CO₂CH₃ i-Bu N═C(SCH₃)₂ CF₃ EXAMPLE 35^(A) 50 43* CF₂H CO₂CH₃ i-Bu CH₂SC(S)N(CH₃)₂ CF₃ EXAMPLE 52^(A) 50 44* CF₂H CO₂CH₃ i-Bu S(CH₂)₂Cl CF₃ SEE EX. 23^(A) 50 45 CF₂H CO₂CH₃ i-Bu COCH₂CO₂C₂H₅ CF₃ U.S. Pat. No. 5,260,262 50 SEE EX. 25 46 CF₂H CO₂CH₃ i-Bu [3-methyl-dihydro CF₃ U.S. Pat. No. 5,129,943 50 2(3H) - thienylidene]amino EXAMPLE 64 47 CF₂H CO₂CH₃ CH═C(CH₃)Ph CO₂CH₃ CF₃ CMPD. 3f^(B) 50 48* CF₃ CO₂C₂H₅ Et NHC(O)NH-[2- CF₂H EXAMPLE 27^(A) 50 (difluoromethyl) - 4-ethyl-5- carbethoxy-6- (trifluoromethyl)- 3-)pyridyl] 49 CF₂H CO₂CH₃ CH₂-i-Bu CO₂CH₃ CF₃ U.S. Pat. No. 4,692,184 50 SEE EX. 14 50 CF₂H CO₂CH₃ i-Bu 1,3-dithian-2-yl CF₃ U.S. Pat. No. 4,988,384 50 EXAMPLE 20 51 CF₃ CO₂C₂H₅ SO₂Ph H CF₃ U.S. Pat. No. 4,655,816 50 EXAMPLE 24 52 CF₃ CO₂CH₃ OC₂H₅ CO₂C₂H₅ CF₃ U.S. Pat. No. 4,698,093 50 EXAMPLE 17 53 CF₃ CO₂C₂H₅ O-i-Pr CH₃ CF₃ U.S. Pat. No. 4,655,816 50 EXAMPLE 37 54* CF₃ CO₂CH₃ O-i-Pr C(O)-[2-(trifluoro- H EXAMPLE 28^(A) 50 methyl)-3-carbo- methoxy-4-i- propoxy-5-pyridyl) 55 CF₂H CO₂CH₃ CH₂-c-Pr C(CN)═[2-(1,3- CF₃ U.S. Pat. No. 5,156,670 50 dioxolanyl)) EXAMPLE 6 56 CF₂H CO₂CH₃ i-Bu CH₂N(CH₃)₂ CF₃ U.S. Pat. No. 5,169,432 50 EXAMPLE 50 57 CF₂H CO₂CH₃ i-Bu 5-methyl-3- CF₃ U.S. Pat. No. 5,125,961 50 isothiazolyl EXAMPLE 17 58 CF₂H CO₂CH₃ i-Bu C(SCH₃)═N-i-Pr CF₃ 55 EXAMPLE 40^(A) 59 CF₂H CO₂CH₃ i-Bu 1,3-dioxan-2-yl CF₃ U.S. Pat. No. 4,988,384 55 EXAMPLE 109 60 CF₂H CO₂CH₃ CH₂-c-Pr CH₂SCH₃ CF₃ U.S. Pat. No. 5,169,432 60 EXAMPLE 47 61 CF₂H CO₂CH₃ i-Bu 1,3-dithiolan-2-yl CF₃ U.S. Pat. No. 4,988,384 60 EXAMPLE 19 62 CF₂H CO₂CH₃ Pr C(O)SC₂H₅ CF₃ U.S. Pat. No. 4,692,184 60 SEE EX. 140 63 CF₂H CO₂CH₃ S-i-Pr CO₂C₂H₅ CF₃ U.S. Pat. No. 4,698,093 60 EXAMPLE 32 64 CF₃ CO₂C₂H₅ OC₂H₅ CN CF₃ U.S. Pat. No. 4,698,093 60 EXAMPLE 25 65 CF₃ CO₂C₂H₅ OC₂H₅ CN OC₂H₅ U.S. Pat. No. 4,609,399 60 EXAMPLE 24 66 CF₂H CO₂CH₃ c-Bu SC₂H₅ CF₃ U.S. Pat. No. 4,789,395 60 EXAMPLE 76 67 CF₂H CO₂CH₃ CH₂-[2- CO₂CH₃ CF₃ EXAMPLE 20^(A) 60 (methylthio) -4- pyrimidinyl] 68 CF₂H CO₂CH₃ i-Pr C(SCH₃)═NCH₃ CF₃ SEE EX. 40^(A) 65 69 CF₂H CO₂CH₃ i-Bu C(O)SCH₃ CF₃ U.S. Pat. No. 4,692,184 65 SEE EX. 140 70* CF₂H CO₂CH₃ c-Bu 1-pyrrolyl CF₃ EXAMPLE 29^(A) 65 71 CF₂H CO₂CH₃ CH₂-c-Pr N(CH₃)₂ CF₃ U.S. Pat. No. 5,037,469 70 EXAMPLE 7 72 CF₂ CO₂C₂H₅ CH₂SCH₃ CO₂C₂H₅ CF₃ U.S. Pat. No. 4,692,184 70 SEE EX. 6 73 CF₂H CO₂CH₃ CH₂S-i-Pr CO₂C₂H₅ CF₃ U.S. Pat. No. 4,692,184 70 SEE EX. 162 74 CF₂H CO₂CH₃ CH═C(C₂H₅)₂ CO₂CH₃ CF₃ SEE CMPD. 3d^(B) 70 75* CF₃ CO₂CH₃ i-Bu C(O)NHCH₂-(4- CF₂H U.S. Pat. No. 4,692,184 70 chlorophenyl) SEE EX. 89 76 CF₃ CO₂C₂H₅ Br CO₂C₂H₅ CF₃ U.S. Pat. No. 4,698,093 70 EXAMPLE 104 77* CF₂H CO₂CH₃ i-Bu C(O)C(S)NH₂ CF₃ EXAMPLE 30^(A) 70 78 CF₂H CO₂CH₃ Et N₃ CF₃ U.S. Pat. No. 4,885,026 70 EXAMPLE 129 79* CF₂H CO₂CH₃ i-Bu CH₂SC(O)N(CH₃)₂ CF₃ EXAMPLE 53^(A) 75 80 CF₂H CO₂CH₃ C(CH₃)₂SCH₃ CO₂C₂H₅ CF₃ U.S. Pat. No. 4,692,184 80 EXAMPLE 170 81 CF₂H CO₂CH₃ i-Bu C(O)-(2-chloro-5- CF₃ U.S. Pat. No. 5,260,262 80 thiazolyl) EXAMPLE 58 82 CF₃ CO₂C₂H₅ 2-thienyl CO₂C₂H₅ CF₃ U.S. Pat. No. 4,692,184 80 EXAMPLE 5 83 CF₂H CO₂CH₃ i-Bu CH₂Cl CF₃ U.S. Pat. No. 5,169,432 80 EXAMPLE 3 84 CF₃ CO₂CH₃ SCH₃ SCH₃ CF₃ U.S. Pat. No. 4,789,395 85 EXAMPLE 42 85* CF₃H CO₂CH₃ NH-i-Pr C(O)P(O)(OC₂H₅)₂ CF₃ EXAMPLE 33^(A) 90 86 CF₃ CO₂-i- Et CO₂-i-Pr CF₃ U.S. Pat. No. 4,692,184 90 Pr EXAMPLE 60 87 CF₂H CO₂CH₃ CH₂-c-Pr CH₂SC₂H₅ CF₃ U.S. Pat. No. 5,169,432 90 EXAMPLE 51 88 CF₃ CO₂CH₃ i-Bu 2-thiazolyl CF₃ U.S. Pat. No. 4,988,384 90 EXAMPLE 44 89 CF₂H CO₂CH₃ i-Bu CH(OH)-(2- CF₃ U.S. Pat. No. 5,260,262 100 thienyl) SEE EX. H 90 CF₃H CO₂CH₃ i-Bu C(═NH)SC₂H₅ CF₃ SEE EX. 46^(A) 100 91 CF₃H CO₂CH₃ CH₂I CO₂CH₃ CF₃ U.S. Pat. No. 4,692,184 100 EXAMPLE 132 92* CH₂OCH₃ CO₂CH₃ Pr CO₂CH₃ CH₂OCH₃ EXAMPLE 32^(A) 100 93 CF₂H CO₂CH₃ i-Bu 5-methoxy-2- CF₃ U.S. Pat. No. 4,988,384 100 oxazolyl EXAMPLE 33 94 CF₃ CO₂C₂H₅ SC₂H₅ H CF₃ U.S. Pat. No. 4,655,816 100 EXAMPLE 25 95 CF₂H CO₂CH₃ CH(i-Pr) CO₂CH₃ CF₃ CMPD. 7b^(B) 100 CO₂CH₃ 96 CH₃ OH CO₂C₂H₅ CO₂C₂H₅ CH₃ CHEM. PHARM. 100 BUL.,14,18 (1966) ^(A)These examples correspond to the examples contained in the present application. ^(B)J. Heterocyclic Chem., 26, 1771 (1989).

TABLE 2 (T-2)

Procedure % Transfer Compound R₂ R₃ R₄ R₅ R₆ Reference @ 100 μm^(c)  97 CF₂H CO₂CH₃ i-Bu 3-methyl-2- CF₃ U.S. Pat. No. 4,988,384 59 oxazolidinyl EXAMPLE 14  98 CF₂H CO3CH₃ i-Pr 4,5-dihydro-2- CF₃ U.S. Pat. No. 4,988,384 63 oxazolyl EXAMPLE 32  99 CF₂H CO₂CH₃ i-Bu C(O)NHBu CF₃ U.S. Pat. No. 4,692,184 66 SEE EX. 192 100 CF₂H CO₂CH₃ i-Bu NHC(O)CH₂Cl CF₃ U.S. Pat. No. 5,114,469 68 SEE EX. 4 101* CF₃ CO₂C₂H₅ OH CO₂-i-Pr H 71 EXAMPLE 41^(A) 102 CH₃ CO₂C₂H₅ CO₂C₂H₅ OH H BIOKHIMYA, 33, 72 350 (1968) 103* CF₂H CO₂CH₃ i-Bu C(S)NH₂ CF₃ SEE EX. 49^(A) 73 104 CF₃ CO₂C₂H₅ 3-pyridyl CO₂C₂H₅ CF₃ U.S. Pat. No. 4,692,184 74 EXAMPLE 8 105 CF₂H CO₂CH₃ i-Bu CH(OH)-(4- CF₃ U.S. Pat. No. 5,260,262 74 methyl-2 SEE EX. H thiazolyl) 106 CH₃ CO₂CH₃ i-Bu CO₂CH₃ CH₃ SEE FOOTNOTE E 74 107* CF₂H CO₂CH₃ CH₂-c-Pr 1-hydroxy-5- CF₃ 75 methyl-3- EXAMPLE 42^(A) pyrrolidinyl 108 CF₃ CO₂C₂H₅ OC₂H₅ CONH₂ CF₃ U.S. Pat. No. 4,698,093 76 EXAMPLE 20 109* CF₃ CO₂C₂H₅ OH OPh H 76 EXAMPLE 43^(A) 110 CF₂H CO₂CH₃ i-Bu 2-oxazolyl CF₃ EXAMPLE 44^(A) 76 111* CF₂H CO₂CH₃ i-Bu S(O)(CH₂)₂Cl CF₃ EXAMPLE 45^(A) 78 112 CF₂H CO₂CH₃ CH₂-c-Pr C(═NH)SCH₃ CF₃ EXAMPLE 46^(A) 78 113 CF₃ CO₂C₂H₅ 4-pyridyl CO₂C₂H₅ CF₃ U.S. Pat. No. 4,692,184 80 EXAMPLE 9 114* CF₃ CO₂C₂H₅ OH OC₂H₅ H EXAMPLE 47^(A) 81 115 CF₂H CO₂CH₃ c-Bu S(O)C₂H₅ CF₃ U.S. Pat. No. 4,789,395 82 EXAMPLE 74 116 CF₃ CO₂CH₃ OH H CO₂CH₃ J. AGRIC. 82 CHEM. 39, p. 1072 (1991) 117* CF₂H CO₂CH₃ i-Bu NHC(O)-[2-chloro- CF₃ EXAMPLE 48^(A) 83 4-(trifluoromethyl)- 5-thiazolyl)] 118 CF₂H CO₂CH₃ i-Bu (1,3-oxathiolan-2- CF₃ U.S. Pat. No. 5,129,943 83 ylidene)amino EXAMPLE 41 119* CF₂H CO₂CH₃ c-Bu C(S)NH₂ CF₃ EXAMPLE 49^(A) 84 120 CF₂H CO₂CH₃ Pr CO₂CH₃ CF₃ U.S. Pat. No. 4,692,184 84 EXAMPLE 67 121* CF₃ CO₂C₂H₅ O-i-Pr H H EXAMPLE 41^(A) 88 122 CH₃ CO₂CH₃ Pr CO₂CH₃ CH₃ ANN, 246, p.32 88 (1888) 123 CF₂H CO₂CH₃ NH-i-Pr C(═NCH₃)SCH₃ CF₃ U.S. Pat. No. 4,698,093 88 EXAMPLE 225 124 CF₂H CO₂CH₃ CH₂-c-Pr 5-oxazolyl CF₃ U.S. Pat. No. 4,988,284 89 SEE EX. 92 125* CF₃ CO₂C₂H₅ OH CO₂C₂H₅ H SEE EX. 41^(A) 89 126 CF₃ CO₂H S-(4-i- CH₃ CF₃ EXAMPLE 50^(A) 90 propylphenyl) 127* CF₃ CO₂CH₃ O-i-Pr H H SEE EX. 41^(A) 90 128 OH CO₂C₂H₅ H CO₂C₂H₅ OH SEE FOOTNOTE F 92 129 CF₃ CO₂CH₃ OP(O) H CF₃ U.S. Pat. No. 4,655,816 92 (OC₂H₅)₂ EXAMPLE 18 130 CH₃ CO₂C₂H₅ CO₂C₂H₅ OH H HCl BIOKHIMYA, 33, 94 salt 350 (1968) 131 CF₂H CO₂CH₃ i-Bu CH(OH)-(3,5- CF₃ U.S. Pat. No. 5,260,262 93 dimethyl-4- SEE EX. H isoxazolyl) 132 CH₃ CO₂CH₃ H CO₂CH₃ CH₃ ANN, 241, p.1 94 (1882) 133 CF₂H CO₂CH₃ i-Bu CH(OH)-(2- CF₃ U.S. Pat. No. 5,260,262 95 thiazolyl) SEE EX. H 134* CF₂H CO₂CH₃ i-Bu C(O)S(CH₂)₂NH₂ CF₃ EXAMPLE 51^(B) 96 135 CF₃ CO₂C₂H₅ OCH₃ Br CF₃ U.S. Pat. No. 4,885,026 97 EXAMPLE 140 136* CF₃ CO₂C₂H₅ H CO₂C₂H₅ CF₃ U.S. Pat. No. 4,692,184 97 SEE EX. 1 137 CF₂H CONH₂ Et CO₂C₂H₅ CF₃ U.S. Pat. No. 4,692,184 98 EXAMPLE 88 138 CF₃ CO₂CH₃ O-i-Pr S(O)₂Ph CF₃ U.S. Pat. No. 4,789,395 98 EXAMPLE 47 139 CF₂H CO₂CH₂CN i-Bu 3,4-dihydro-2 CF₃ U.S. Pat. No. 4,988,384 98 thiazolyl EXAMPLE 88 140 CF₂H CO₂CH₃ i-Bu CH═NOH CF₃ U.S. Pat. No. 5,125,961 99 EXAMPLE C 141 CF₂H CO₂CH₃ i-Bu 4,5-dihydro-1H-2- CF₃ U.S. Pat. No. 4,988,384 99 imidazoly)- EXAMPLE 12 142 CF₂H CO₂CH₃ i-Bu N(CH₃)C(O)- CF₃ U.S. Pat. No. 5,037,469 99.5 c-Pr EXAMPLE J1 143 CF₃ CO₂CH₃ OH H CF₃ U.S. Pat. No. 4,655,816 99.7 EXAMPLE 4 144 CF₂H CO₂CH₃ i-Bu CONH₂ CF₃ RES. DTSCL., 94 295, 867(1988) 145* CF₂H CO₂CH₃ i-Bu SCH₂C(O)NH₂ CF₃ EXAMPLE 23^(A) 64 146* CF₂H CO₂CH₃ i-Bu SCH(CH₃)OC₂H₅ CF₃ EXAMPLE 23^(A) 67^(D) 147* CF₂H CO₂CH₃ i-Bu SCH(CH₃)OCH₃ CF₃ EXAMPLE 23^(A) 15^(D) 148* CF₂H CO₂CH₃ i-Bu S(CH₂)₂F CF₃ EXAMPLE 2^(A) 32^(D) 149* CF₂H CO₂CH₃ i-Bu SC(O)CH₃ CF₃ SEE EX. 23^(A) 31^(D) 150* CF₂H CO₂CH₃ i-Bu S-(tetrahydro-2- CF₃ EXAMPLE 31^(A) 95^(D) furyl) ^(A)These examples correspond to the examples contained in the present application. ^(B)J. Heterocyclic Chem., 26, 1771 (1989). ^(C)All compounds in Table 2 exhibited an IC₅₀ greater than or equal to 100 μm when tested. ^(D)% transfer at 10 μm. ^(E)Compound 106 is prepared according to a procedure similar to that disclosed in Ann., 246, p. 32 except using isovaleraldehyde as the reagent. ^(F)Compound 128 is prepared according to a procedure similar to that disclosed in Collect. Czech. Chem. Commun., 34, p. 427-441 (1969) except using ethyl cyanoacetate as the reagent instead of methyl cyanoacetate.

TABLE 3

Compound X Y₁ Y₂ Y₃ Y₄ Y₅ mp (° C.) IC₅₀ (μm) 151* S H t-Bu H t-Bu H 102.5-108.5    60 152* S Me H Me H  98.5-102.5    60 153* S OMe H H H H 100-102   100 154* S H OMe H H H   87-88.5   100 155* S t-Bu H t-Hu H H 115.5-120.5    50 156* S H H t-Bu H H 60.5-62.5   100 157* S i-Pr H H H H —    60 158* S H Me H Me H 96-99   100 159* S H H SMe H H 112-114    80 160* S CH₂-(4- H i-Pr H H 86.5-91      60 fluorophenyl) 161* S CH₂-(4- H F H H 105-107    70 fluorophenyl) 162* S H H Cl H H   94-96.5    50 163* S Cl H H Cl H 112.5-113.5    65 164* S Cl H H H Cl 109.5-112.5    50 165* O H OMe H H H 74-75 >100^(A) 166* O NO₂ H H H H 102.5-105.5 >100^(B) 167* O H t-Bu H t-Bu H   100-103.5    60 168* O t-Bu H t-Bu H H —    60 165* O H H t-Bu H H —    70 170* O CH₂-(4- H i-Pr H H 102-104    40 fluorophenyl) 171* O CH₂-(4- OMe OHe OHe H 131.5-133.5    70 fluorophenyl) 172* O OMe H H H H   73-74.5 >100^(C) 173* O H H Cl H H 81.5-82.5    45 174* O H Me H Me H 90.5-94      60 175* O iPr H H H H — >100^(D) 176* O Me H NO₂ H Me 96-97   100 177* O Me H Me H H 95-99    70 ^(A)89% CE transferred @ 100 μm. ^(B)84% CE transferred @ 100 μm. ^(C)71% CE transferred @ 100 μm. ^(D)58% CE transferred @ 100 μm.

TABLE 4 COMPOUND Mp (°C.) IC₅₀ (μm) 178*

mp 125-127.5 IC₅₀ = 70 μm 179*

mp 110-115 IC₅₀ = 60 μm

TABLE 5 (T-5)

Compound R₂ R₃ R₄ R₅ R₆ X IC₅₀ 180* CF₂H CO₂CH₃ i-Bu 4-t-butylphenyl CF₃ S 0.45 181* CF₂H CO₂CH₃ i-Bu 2-(difluoromethyl)-3- CF₃ S 1.5 carbomethoxy-4- i-butyl-6- (trifluoromethyl)-5- pyridyl 182* CF₂H CO₂CH₃ i-Bu 2-(difluoromethyl)-3- CF₃ CH₂ 19 carbomethoxy-4- i-butyl-6- (trifluoromethyl)-5- pyridyl 183* CF₂H CO₂CH₃ i-Bu 2-(difluoromethyl)-3- CF₃ C(O) 50 carbomethoxy-4- i-butyl-6- (trifluoromethyl)-5- pyridyl

TABLE 6 (T-6)

Compound R IC₅₀ (μm) 184* 3-bromophenyl    30 185* 4-chlorophenyl    10 186* 2,3,5,6-tetrafluorophenyl    50 187* 3,5-di-t-butylphenyl    40 188* 2-(1-methyl imidazolyl) >100^(A) 189* 5-(1-methyltetrazolyl) >100^(A) 190* 2-(5-nitrobenzoimidazolyl)    25 191* 4-(trifluoromethoxy)phenyl    10 192* 2-quinolinyl    40 193* 4-bromophenyl    20 194* pentafluorophenyl    30 195* 2,5-dichlorophenyl    50 196* 2,3,5,6-tetrafluoro-4-    20 (trifluoromethyl)phenyl 197* 2-(4-methylpyrimidinyl)    60 198* 4-nitrophenyl    7 199* 4-methoxyphenyl    20 200* 2-chlorophenyl    40 201* 2,6-dichlorophenyl    30 202* 8-quinolinyl    80 203* 2-pyrimidinyl    70 204* 4-(acetylamino)phenyl >100^(B) 205* 2-benzoxazolyl    20 206* 4-bromo-2-    50 (trifluoromethoxy)phenyl 207* 3-aminophenyl   100 208* 2-methoxyphenyl    60 209* 2-(5-methylbenzimidazolyl)    10 210* benzoimidazol-2-yl    20 211* 3-methoxyphenyl    45 212* 2-benzothiazolyl    15 213* 3-chlorophenyl    15 214* 3,4-dichlorophenyl    2 215* 2-naphthyl    2 216* 2-pyridyl    40 217* 2-bromophenyl    50 218* [3-(carbomethoxy)-2-    30 (difluoromethyl)-4-isobutyl- 6-(trifluoromethyl)-5- pyridyl]methyl ^(A)90% CE transferred @ 100 μm. ^(B)80% CE transferred @ 100 μm.

TABLE 7 (T-7)

Compound R IC₅₀ (μm) 219 phenyl 25 220 4-chlorophenyl 20 221 4-methoxyphenyl 40 222 3,4-dibenzyloxyphenyl 15 223 2-nitrophenyl 50 224 4-benzyloxyphenyl 25 225 4-biphenyl 10  226* 2-chloro-3,4-methylenedioxyphenyl 60 227 9-anthryl 30 228 3,5-bis(trifluoromethyl)phenyl 50 229 3-bromophenyl 50 230 3-nitrophenyl 50 231 3-methoxyphenyl 50 232 4-t-butyiphenyl 35  233* 2-pyridyl 60 234 2,4-bis(trifluoromethyl)phenyl 20 235 4-(trifluoromethoxy)phenyl 30 236 3,4-dichlorophenyl 40 237 2,4-dichlorophenyl 30 238 1-naphthyl 45 239 2-bromophenyl 45 240 2,6-dichlorophenyl 50  241* 2-quinolinyl 50 242 3-phenoxyphenyl 20 243 3,5-dichlorophenyl 50 244 pentafluorophenyl 50  245* 1,2,3,4-tetrahydro-1,1,4,4- 30 teoramethyl-6-naphthyl  246* 8-(6-chloro-1,3-benzodioxanyl) 30

TABLE 8 Compound Number Structure IC₅₀ (μM) 247

5 248

77 249

5 250

40 251

7 252

4.5 253

19 254

55 255

256

257

258

15 259

60 260

261

262

263

40 264

30 265

60 266

>100 267

70 268

70 269

>100 270

>100 271

70 272

90 273

100 274

8 275

>100 276

>100 277

278

80 279

15 280

>100 281

>100 282

283

38.7 284

22.7 285

286

11.7 287

288

19 289

55.3 290

12.2 291

292

16.2 293

10.2 294

40 295

>100 296

>100 297

>100

In yet another embodiment, the method comprises the administration of a therapeutically effective amount of the compound of Formula IA wherein:

R₂ is selected from the group consisting of alkyl and fluorinated alkyl;

R₃ is selected from the group consisting of —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen and alkyl;

R₄ is selected from the group consisting of alkyl, cycloalkyl, arylcarbonyloxy, thio, arylthio, and heterocyclylthio,

R₅ is selected from the group consisting of alkyl, heterocyclyl, arylthioalkyl, heteroarylthioalkyl,

—CO₂R₁₄,

wherein R₁₄ is alkyl;

wherein R_(15b) is hydroxy, and

R_(16b) is heteroaryl;

wherein R₁₉ is —SR₂₀, and R₂₀ is alkyl;

wherein R₃₉ is alkoxy, and

R₄₀ is haloalkyl;

—N═R₄₁,

wherein R₄₁ is heterocyclylidenyl;

—N═S═O;

—SR₄₅,

wherein R₄₅ is selected from the group consisting of hydrogen, —SR₄₆, and —CH₂R₄₇,

wherein R₄₆ is selected from the group consisting of aryl and heteroaryl, and

R₄₇ is selected from the group consisting of aryl and heteroaryl; and

wherein R₅₀ is selected from the group consisting of alkyl and alkoxy;

R₆ is selected from the group consisting of alkyl and fluorinated alkyl;

or a pharmaceutically acceptable salt or tautomer thereof;

provided that:

when R₂ is trifluoromethyl, R₃ is CO₂CH₃, R₄ is isobutyl, and R₅ is —CO₂CH₃, then R₆ is selected from the group consisting of alkyl comprising at least two carbon atoms and fluorinated alkyl.

In yet another embodiment, the method comprises the administration of a therapeutically effective amount of the compound of Formula IA which is selected from the compounds disclosed below:

Methyl 5-[(4-t-Butylphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl))-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 180);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(palmitoylthio)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 5);

Methyl 2-(Difluoromethyl)-5-(methoxycarbonylthio)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 6);

Diethyl 2,6-Bis(trifluoromethyl)-4-(trimethylsilyl)-3,5-pyridinedicarboxylate (Compound 31);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(methylthiomethylthio)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 33);

Methyl 5-(1-Bromo-2-methoxyethenyl)-4-(cyclopropylmethyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 35);

Methyl 5-(Chloroethylthio)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 44);

Methyl 4-(i-Propoxy)-5-{[3-(methoxycarbonyl)-4-(i-propoxy-)-6-(trifluoromethyl)-5-pyridyl]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 54);

Methyl 2-(Difluoromethyl)-4-cyclobutyl-5-(1-pyrrolyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 70);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(aminothionocarbonyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 77);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(dimethylamino)carbonyl]thiomethyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 79);

Methyl 2-(Difluoromethyl)-5-[(diethylphosphono) carbonyl]-4-(i-propylamino)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 85);

Dimethyl 2,6-Bis(methoxymethyl)-4-propyl-3,5-pyridinecarboxylate (Compound 92);

Methyl 5-[(Aminocarbonyl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 145);

Methyl 2-(Difluoromethyl)-5-(1-ethoxyethylthio)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 146);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(1-methoxyethylthio)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 147);

Methyl 2-(Difluoromethyl)-5-(2-fluoroethylthio)4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 148);

Methyl 5-(Acetylthio)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 149);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(2-tetrhydrofurylthio)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 150);

Methyl 2-(Difluoromethyl)-5-{[(3,5-di-t-butylphenyl) thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 151);

Methyl 2-(Difluoromethyl)-5-{[(2,4-dimethylphenyl) thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 152);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-methoxyphenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 153);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(3-methoxyphenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 154);

Methyl 2-(Difluoromethyl)-5-{[(2,4-di-t-butylphenyl) thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 155);

Methyl 5-{[(4-t-Butylphenyl)thio]carbonyl}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 156);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-isopropylphenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 157);

Methyl 2-(Difluoromethyl)-5-{[(3,5-dimethylphenyl) thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 158);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(4-methylthiophenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 159);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-(4-fluorobenzyl)-4-isopropylphenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 160);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-(4-fluorobenzyl)-4-fluorophenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 161);

Methyl 5-{[(4-chlorophenyl)thio]carbonyl}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 162);

Methyl 5-{[(2,5-Dichlorophenyl)thio]carbonyl}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 163);

Methyl 5-{[(2,6-Dichlorophenyl)thio]carbonyl}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 164);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-naphthyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 178);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(1-naphthyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 179);

3-Methyl 5-(3-Methoxyphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 165);

3-Methyl 5-(2-Nitrophenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 166);

3-Methyl 5-(3,5-Di-t-butylphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 167);

3-Methyl 5-(2,4-Di-t-butylphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 168);

3-Methyl 5-(4-t-Butylphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 169);

3-Methyl 5-[2-(4-Fluorobenzyl)-4-isopropylphenyl]2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 170);

3-Methyl 5-[2-(4-Fluorobenzyl)-3,4,5-(trimethoxy) phenyl]2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 171);

3-Methyl 5-(2-Methoxyphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 172);

3-Methyl 5-(4-Chlorophenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 173);

3-Methyl 5-(3,5-Dimethylphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 174);

3-Methyl 5-(2-Isopropylphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 175);

3-Methyl 5-(2,6-Dimethyl-4-nitrophenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 176);

3-Methyl 5-(2,4-Dimethylphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 177);

Methyl 5-(4-t-Butylphenyldithio)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 180);

Dimethyl 5,5′-Dithiobis[2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate](Compound 181);

Methyl 5-{[2-(Difluoromethyl)-4-(2-methylpropyl)-3-(methoxycarbonyl)-6-(trifluoromethyl)-5-pyridyl]methylthio}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 182);

Methyl 5-{[2-(Difluoromethyl)-4-(2-methylpropyl)-3-(methoxycarbonyl)-6-(trifluoromethyl)-5-pyridyl]carbonylthio}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 183);

Methyl 5-[(3-Bromophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 184);

Methyl 5-[(4-Chlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 185);

Methyl 5-[(2,3,5,6-Tetrafluorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 186);

Methyl 5-[(3,5-Di-t-butylphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 187);

Methyl 5-[(1-Methylimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 188);

Methyl 5-[(1-Methyltetrazol-5-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 189);

Methyl 5-[(5-Nitrobenzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 190);

Methyl 5-[(4-(Trifluoromethoxy)phenyl))thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 191);

Methyl 5-[(Quinolin-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 192);

Methyl 5-[(4-Bromophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl) -3-pyridinecarboxylate (Compound 193);

Methyl 5-[(Pentafluorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 194);

Methyl 5-[(2,5-Dichlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 195);

Methyl 5-[(2,3,5,6-Tetrafluoro-4-(trifluoromethyl) phenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 196);

Methyl 5-[(4-Methylpyrimidin-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 197);

Methyl 5-[(4-Nitrophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 198);

Methyl 5-[(4-Methoxyphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 199);

Methyl 5-[(2-Chlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 200);

Methyl 5-[(2,6-Dichlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 201);

Methyl 5-[(Quinolin-8-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 202);

Methyl 5-[(Pyrimidin-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 203);

Methyl 5-[(4-(Acetylamino)phenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 204);

Methyl 5-[(Benzoxazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 205);

Methyl 5-[(4-Bromo-2-(trifluoromethoxy)phenyl) thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 206);

Methyl 5-[(3-Aminophenyl)thiomethyl)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 207);

Methyl 5-[(2-Methoxyphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 208);

Methyl 5-[(5-Methylbenzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 209);

Methyl 5-[(Benzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 210);

Methyl 5-[(3-Methoxyphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 211);

Methyl 5-[(Benzothiazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 212);

Methyl 5-[(3-Chlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 213);

Methyl 5-[(3,4-Dichlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 214);

Methyl 5-[(2-Naphthyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 215);

Methyl 5-[(2-Pyridyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 216);

Methyl 5-[(2-bromophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 217);

Bis{3-(carbomethoxy)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-5-pyridyl]methyl Sulfide (Compound 218);

Methyl 5-[(2-Chloro-3,4-methylenedioxyphenyl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 226);

Methyl 5-[(2-pyridyl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 233);

Methyl 5-[(2-quinolinyl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 241);

Methyl 5-[(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)methylthio]-2-(difluoromethyl)-4-(2-methyl-propyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 245);

Methyl 5[(6-chloro-1,3-benzodioxan-8-yl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 246);

Diethyl 5,5′-(Carbonyldiimino)bis[6(difluoromethyl)-4-ethyl-2-(trifluoromethyl)-3-pyridinecarboxylate (Compound 48);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(dimethylamino)thiono]thiomethyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 43);

2-(Difluoromethyl)-5-hydroxymethyl-4-phenyl-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]hydroxymethyl}pyridine;

2-(Difluoromethyl)-5-hydroxymethyl-4-phenyl-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]carbonyl}pyridine;

2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]hydroxymethyl}pyridine;

2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]carbonyl}pyridine;

2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]fluoromethyl}pyridine;

2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]fluoromethyl}pyridine;

2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-(2-naphthylfluoromethyl)pyridine;

2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]mercaptomethyl}pyridine;

2-(Difluoromethyl)-5-hydroxymethyl-4-phenyl-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]mercaptomethyl}pyridine;

2-(Cyclopentyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]carbonyl}pyridine;

2-(1-Pyrrolidinyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]carbonyl}pyridine;

2-(1-Pyrrolidinyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]hydroxymethyl}pyridine; and

2-(1-Pyrrolidinyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]fluoromethyl}pyridine.

In yet another embodiment, the method comprises the administration of a therapeutically effective amount of the compound of Formula IA which is selected from the compounds disclosed below:

Methyl 5-(4-t-Butylphenyldithio)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Dimethyl 5,5′-Dithiobis[2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 5-[(3,4-Dichlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 2-(Difluoromethyl)-5-isothiocyanato-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 5-[(2-Naphthyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 2-(difluoromethyl)-5-mercapto-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

5-Ethyl 3-Methyl 2-(difluoromethyl)-4-[(4,5-dihydro-2-thiazolyl)thio]-6-(trifluoromethyl)-3,5-pyridinedicarboxylate;

Methyl 5-[(4-Nitrophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(palmitoylthio)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 2-(Difluoromethyl)-5-(methoxycarbonylthio)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 5-[(4-t-Butylphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl))-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 2-(Difluoromethyl)-5-[(1,4-dithian-2-ylidene)amino]-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 5-[(4-(Trifluoromethoxy)phenyl))thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 5-[(4-Chlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 5-[(5-Methylbenzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 5-[(Benzothiazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 5-[(3-Chlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 5-{[3-(Carbomethoxy)-2-(difluoromethyl)-4-isobutyl-6-(trifluoromethyl)-5-pyridyl]thiomethyl}-2-(difluoromethyl)-4-isobutyl-6-(trifluoromethyl)-3-pyridinecarboxylate;

Di-t-Butyl 2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate;

Methyl 5-[(4-Bromophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 5-[(2,3,5,6-Tetrafluoro-4-(trifluoromethyl)phenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 5-[(4-Methoxyphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 5-[(Benzoxazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 5-[(Benzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(4,5-dihydro-2-thiazoyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Ethyl 2,6-Bis(trifluoromethyl)-5-methyl-4-[4-(trifluoromethylphenyl)carbonyloxy]-3-pyridinecarboxylate;

Methyl 2-(Difluoromethyl)-5-[(i-propylthio)carbonyl]-4-(cyclobutyl)-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 4-(4-i-Propylphenylthio)-5-methyl-6-(trifluoromethyl)-3-pyridinecarboxylate;

Methyl 5-[(5-Nitrobenzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate; and

In yet another embodiment, the method comprises the administration of a therapeutically effective amount of the compound of Formula IA which is Dimethyl 5,5′-dithiobis[2-difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate].

In still another embodiment, the method comprises the administration of a therapeutically effective amount of the compound of Formula IB:

wherein:

R₂ and R₆ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R₂ and R₆ is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;

R₃ is selected from the group consisting of hydroxy, amido, arylcarbonyl, heteroarylcarbonyl, hydroxymethyl

—CHO,

—CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen, alkyl and cyanoalkyl; and

wherein R_(15a) is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy, and

R_(16a) is selected from the group consisting of alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl, and heterocyclyl, arylalkoxy, trialkylsilyloxy;

R₄ is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkanoyloxy, alkenoyloxy, alkynoyloxy, aryloyloxy, heteroaroyloxy, heterocyclyloyloxy, alkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, heterocyclyloxycarbonyl, thio, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, heterocyclylamino, aryldialkylamino, diarylamino, diheteroarylamino, alkylarylamino, alkylheteroarylamino, arylheteroarylamino, trialkylsilyl, trialkenylsilyl, triarylsilyl,

—OC(O)N(R_(8a)R_(8b)), wherein R_(8a) and R_(8b) are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,

—SO₂R₉, wherein R₉ is selected from the group consisting of hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl,

—OP(O)(OR_(10a))(OR_(10b)), wherein R_(10a) and R_(10b) are independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and

—OP(S)(OR_(11a))(OR_(11b)), wherein R_(11a) and R_(11b) are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

R₅ is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl, arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl, heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkenyl, alkenoxyalkenyl, alkynoxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl, heterocyclyloxyalkenyl, cyano, hydroxymethyl,

—CO₂R₁₄,

wherein R₁₄ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

wherein R_(15b) is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy, and

R_(16b) is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, and trialkylsilyloxy;

wherein R₁₇ and R₁₈ are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

wherein R₁₉ is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —SR₂₀, —OR₂₁, and —R₂₂CO₂R₂₃, wherein

R₂₀ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocyclyl, alkylheteroarylamino, arylheteroarylamino,

R₂₁ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl,

R₂₂ is selected from the group consisting of alkylene or arylene, and

R₂₃ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R₂₄ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, aralkenyl, and aralkynyl;

wherein R₂₅ is heterocyclylidenyl;

wherein R₂₆ and R₂₇ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R₂₈ and R₂₉ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R₃₀ and R₃₁ are independently alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy; and

wherein R₃₂ and R₃₃ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

 —C≡C—Si(R₃₆)₃,

wherein R₃₆ is selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl and heterocyclyl;

wherein R₃₇ and R₃₈ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl;

wherein R₃₉ is selected from the group consisting of hydrogen, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio, and

R₄₀ is selected from the group consisting of haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy, heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio and heterocyclylthio;

—N═R₄₁,

wherein R₄₁ is heterocyclylidenyl;

wherein R₄₂ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl, and

R₄₃ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, and haloheterocyclyl;

wherein R₄₄ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

—N═S═O;

—N═C═S;

—N═C═O;

—N₃;

—SR₄₅,

wherein R₄₅ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl, aminocarbonylaryl, aminocarbonylheteroaryl, and aminocarbonylheterocyclyl, —SR₄₆, and —CH₂R₄₇,

wherein R₄₆ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and

R₄₇ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl; and

wherein R₄₈ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl, and

R₄₉ is selected from the group consisting of alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl;

wherein R₅₀ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy and heterocyclyloxy;

wherein R₅₁ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl and haloheterocyclyl; and

wherein R₅₃ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl;

or a pharmaceutically acceptable salt or tautomer thereof,

provided that when R₅ is selected from the group consisting of heterocyclylalkyl and heterocyclylalkenyl, the heterocyclyl radical of the corresponding heterocyclylalkyl or heterocyclylalkenyl is other than a δ-lactone; and

provided that when R₄ is aryl, heteroaryl or heterocyclyl, and one of R₂ and R₆ is trifluoromethyl, then the other of R₂ and R₆ is difluoromethyl.

Novel Compounds

The present invention also relates to a class of novel substituted pyridines which are beneficial in the therapeutic and prophylactic treatment of CTEP-mediated disorders (such as coronary artery disease) as given in Formula IIA:

wherein:

R₂ and R₆ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R₂ and R₆ is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;

R₃ is selected from the group consisting of arylcarbonyl, heteroarylcarbonyl, hydroxymethyl, arylalkoxyalkyl, trialkylsilyloxyalkyl,

—CHO,

—CO₂R₇,

wherein R₇ is selected from the group consisting of hydrogen and alkyl (preferably methyl or ethyl); and

wherein R_(15a) is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, and

R_(16a) is selected from the group consisting of alkyl, haloalkyl, alkenyl, aryl and heteroaryl;

R₄ is selected from the group consisting of hydrogen, hydroxy, alkyl, aryl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, alkoxy, thio, trialkylsilyl, alkylamino, and —OC(O)N(R₈)₂, wherein R₈ is aryl;

R₅ is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aralkyl, alkoxy, aryloxy, cycloalkylthioalkyl, arylthioalkyl, heteroarylthioalkyl, alkoxyalkenyl, arylcarbonyloxyalkyl, pyrrolyl, substituted pyrrolidinyl, hydroxymethyl, arylalkoxyalkyl, and trialkylsilyloxyalkyl,

—CO₂R₁₄,

wherein R₁₄ is alkyl;

wherein R_(15b) is selected from the group consisting of hydroxy, halogen, alkoxy, and alkylthio, aroyloxy, and alkylsulfonyloxy, and

R_(16b) is selected from the group consisting of alkyl, alkenyl, aryl, and heteroaryl;

wherein R₁₇ and R₁₈ are independently alkyl;

wherein R₁₉ is aryl, heteroaryl, —SR₂₀, and —OR₂₁,

wherein R₂₀ is selected from the group consisting of aryl, heteroaryl and aminoalkyl, and

R₂₁ is selected from the group consisting of aryl and heteroaryl;

wherein R₂₄ is aralkyl (preferably halo-substituted aralkyl);

wherein R₂₈ and R₂₉ are independently alkyl;

wherein R₃₀ and R₃₁ are independently alkoxy;

—C≡C—Si(R₃₆)₃,

wherein R₃₆ is alkyl;

wherein R₃₇ is selected from the group consisting of hydrogen, alkoxy, and alkylthio, and

R₃₈ is selected from the group consisting of haloalkyl, cycloalkyl, heterocyclylalkoxy, and alkylthio;

provided that when R₃₇ is hydrogen, then R₃₈ is selected from the group consisting of haloalkyl, cycloalkyl, and heterocyclylalkoxy;

wherein R₄₂ is selected from the group consisting of hydrogen and alkyl, and

R₄₃ is substituted heteroaryl;

wherein R₄₄ is selected from the group consisting of aryl and heteroaryl;

—SR₄₅,

wherein R₄₅ is selected from the group consisting of haloalkyl, heterocyclyl, alkylthioalkyl, aminocarbonylalkyl, —SR₄₆, and —CH₂R₄₇,

wherein R₄₆ is selected from the group consisting of aryl (preferably substituted aryl) and heteroaryl (preferably substituted pyridyl), and

R₄₇ is selected from the group consisting of methylenedioxyphenyl, pyridyl, quinolinyl, tetrahydronaphthyl and benzodioxanyl;

wherein R₄₈ is selected from the group consisting of hydrogen and alkyl, and

R₄₉ is selected from the group consisting of alkoxy and haloalkyl;

wherein R₅₀ is selected from the group consisting of alkyl, alkoxy, and heteroaryl (preferably substituted heteroaryl); and

wherein R₅₁ is haloalkyl;

or a pharmaceutically acceptable salt or tautomer thereof,

provided that:

when R₂ is selected from the group consisting of difluoromethyl and trifluoromethyl, R₃ is selected from the group consisting of —CO₂H, —CO₂CH₃ and —CO₂C₂H₅, R₅ is hydrogen, and R₆ is selected from the group consisting of hydrogen and trifluoromethyl, then R₄ is selected from the group consisting of cycloalkyl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, thio, trialkylsilyl, alkylamino, and —OC(O)N(R₈)₂, wherein R₈ is aryl; provided further that when R₂, R₃ and R₅ are as defined above, and R₄ is alkoxy, then R₆ is hydrogen;

when R₂ is selected from the group consisting of fluorinated methyl and chlorofluorinated methyl, R₃ is selected from the group consisting of hydroxymethyl and CO₂R₇, R₅ is selected from the group consisting of hydroxymethyl and CO₂R₁₄, R₆ is selected from the group consisting of fluorinated methyl and chlorofluorinated methyl, and R₇ and R₁₄ are independently alkyl, then R₄ is selected from the group consisting of hydrogen, thio, trialkylsilyl, and —OC(O)N(R₈)₂, wherein R₈ is aryl;

when R₂ is difluoromethyl, R₃ is —CO₂C₂H₅, R₄ is hydrogen, R₅ is —CO₂C₂H₅, then R₆ is selected from the group consisting of monofluoroalkyl, difluoroalkyl and alkoxyalkyl;

when R₂ is trifluoromethyl, R₃ is —CO₂R₇, R₅ is methyl, R₆ is selected from the group consisting of fluorinated methyl, fluorinated ethyl and chlorofluorinated methyl, and R₇ is selected from the group consisting of hydrogen and alkyl, then R₄ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, thio, trialkylsilyl, and —OC(O)N(R₈)₂, wherein R₈ is aryl; and

when R₄ is selected from the group consisting of alkyl, cycloalkyl and cycloalkylalkyl, R₃ is —CO₂R₇, and R₇ is alkyl, then R₅ is other than arylcarbonyl, heteroarylcarbonyl or

wherein R_(16b) is alkyl when R_(15b) is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, or wherein R_(16b) is aryl or heteroaryl when R_(15b) is hydroxy;

when R₄ is selected from the group consisting of alkyl, cycloalkyl and cycloalkylalkyl, R₅ is —CO₂R₁₄, and R₁₄ is alkyl, then R₃ is other than arylcarbonyl, heteroarylcarbonyl or

wherein R_(16a) is alkyl when R_(15a) is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, or wherein R_(16a) is aryl or heteroaryl when R_(15a) is hydroxy; and

when R₂ and R₆ are independently selected from fluorinated methyl and chlorofluorinated methyl, R₃ is CO₂R₇, R₅ is hydroxy, alkoxy or aryloxy, then R₄ is selected from the group consisting of aryl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, thio, trialkylsilyl, alkylamino, and —OC(O)N(R₈)₂, wherein R₈ is aryl; and

when R₄ is aryl and one of R₂ and R₆ is trifluoromethyl, then the other of R₂ and R₆ is difluoromethyl.

In one embodiment, the novel compounds comprise a compound of Formula IIA as described above wherein:

R₂ is fluorinated methyl; and

R₃ is —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen, methyl and ethyl.

The compounds of Formula IIA are capable of inhibiting the activity of cholesteryl ester transfer protein (CETP), and thus could be used in the manufacture of a medicament or a method for the prophylactic or therapeutic treatment of diseases mediated by CETP, such as coronary artery disease, peripheral vascular disease, hyperlipidemia, hypercholesterolemia, and other diseases attributable to either high LDL and low HDL or a combination of both. The compounds of Formula IIA would be also useful in prevention of cerebral vascular accident (CVA) or stroke.

In another embodiment, the novel compounds comprise a compound of Formula IIA wherein:

R₂ is fluorinated alkyl;

R₃ is —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen and alkyl;

R₄ is selected from the group consisting of alkyl and cycloalkyl;

R₅ is selected from the group consisting of:

1-pyrrolyl;

wherein R₃₇ is selected from the group consisting of hydrogen, alkoxy, and alkylthio, and

R₃₈ is selected from the group consisting of haloalkyl, cycloalkyl, heterocyclylalkoxy, and alkylthio;

provided that when R₃₇ is hydrogen, then R₃₈ is selected from the group consisting of haloalkyl, cycloalkyl, and heterocyclylalkoxy;

wherein R₄₂ is selected from the group consisting of hydrogen and alkyl, and

R₄₃ is substituted heteroaryl;

wherein R₄₄ is pyridyl; and

R₆ is fluorinated alkyl;

or a pharmaceutically acceptable salt or tautomer thereof.

In yet another embodiment, the novel compounds comprise a compound of Formula IIA wherein:

R₂ is fluorinated alkyl;

R₃ is —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen and alkyl;

R₄ is alkyl;

R₅ is selected from the group consisting of:

—SR₄₅

wherein R₄₅ is selected from the group consisting of haloalkyl, heterocyclyl, aralkyl, heteroaralkyl, alkylthioalkyl, aminocarbonylalkyl, —SR₄₆, and —CH₂R₄₇,

wherein R₄₆ is selected from the group consisting of aryl (preferably substituted aryl) and heteroaryl (preferably substituted pyridyl), and

R₄₇ is selected from the group consisting of methylenedioxyphenyl, pyridyl, quinolinyl, tetrahydronaphthyl and benzodioxanyl; and

wherein R₄₈ is selected from the group consisting of hydrogen and alkyl, and

R₄₉ is selected from the group consisting of alkoxy and haloalkyl;

wherein R₅₀ is selected from the group consisting of alkyl, alkoxy, and heteroaryl (preferably substituted heteroaryl);

wherein R₅₁ is haloalkyl; and

R₆ is fluorinated alkyl;

or a pharmaceutically acceptable salt or tautomer thereof.

In yet another embodiment, the novel compounds comprise a compound of Formula IIA wherein:

R₂ is fluorinated alkyl;

R₃ is —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen and alkyl;

R₄ is hydroxy, alkoxy, —OC(O)N(R₈)₂, or —OP(O)(OR₁₀)₂, wherein R₈ is aryl and R₁₀ is alkyl;

R₅ is selected from the group consisting of hydrogen, alkoxy and aryloxy; and

R₆ is selected from the group consisting of hydrogen and fluorinated alkyl;

or a pharmaceutically acceptable salt or tautomer thereof;

provided that when R₂ is trifluoromethyl, R₃ is selected from the group consisting of —CO₂CH₃ and —CO₂C₂H₅, R₅ is hydrogen, and R₆ is selected from the group consisting of hydrogen and trifluoromethyl, then R₄ is selected from the group consisting of alkoxy, —OC(O)N(R₈)₂, or —OP(O)(OR₁₀)₂, wherein R₈ is aryl and R₁₀ is alkyl; provided further that when R₂, R₃ and R₅ are as defined above, and R₄ is alkoxy, then R₆ is hydrogen.

In yet another preferred embodiment, the novel compounds comprise a compound of Formula IIA wherein:

R₂ is fluorinated alkyl;

R₃ is —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen and alkyl;

R₄ is selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkylalkyl, arylthio (preferably substituted arylthio), and alkylamino; and

R₅ is selected from the group consisting of alkyl, arylcarbonyloxyalkyl, arylthioalkyl, heteroarylthioalkyl, alkoxyalkenyl (preferably halo-substituted alkoxyalkenyl and more preferably bromo-substituted alkoxyalkenyl), substituted pyrrolidinyl,

wherein R₁₅ is alkoxy, and R₁₆ is heteroaryl;

wherein R₁₇ and R₁₈ are independently alkyl;

wherein R₁₉ is selected from the group consisting of pyridyl, —SR₂₀, and —OR₂₁, wherein R₂₀ is selected from the group consisting of aryl, heteroaryl and aminoalkyl, and R₂₁ is selected from the group consisting of aryl and heteroaryl;

wherein R₂₄ is aralkyl (preferably halo-substituted aralkyl);

wherein R₂₆ and R₂₇ are independently alkyl;

wherein R₂₈ and R₂₉ are independently alkoxy; and

—C≡C—Si(R₁₀)₃,

wherein R₁₀ is alkyl; and

R₆ is selected from the group consisting of hydrogen and fluorinated alkyl;

or a pharmaceutically acceptable salt or tautomer thereof;

provided that:

when R₂ is trifluoromethyl, R₃ is —CO₂C₂H₅, R₄ is isopropoxy, R₅ is methyl, then R₆ is hydrogen; and

when R₅ is alkyl, then R₄ is selected from the group consisting of cycloalkyl, cycloalkylalkyl, arylthio, and alkylamino.

In yet another embodiment, the novel compounds comprise a compound of Formula IIA wherein:

R₂ is selected from the group consisting of fluorinated alkyl and alkoxyalkyl;

R₃ is —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen and alkyl;

R₄ is selected from the group consisting of hydrogen, hydroxy, alkyl, heteroarylalkyl, thio, and trialkylsilyl;

R₅ is CO₂R₁₄, wherein R₁₄ is alkyl; and

R₆ is selected from the group consisting of hydrogen, fluorinated alkyl, and alkoxyalkyl;

or a pharmaceutically acceptable salt or tautomer thereof;

provided that when R₂ is difluoromethyl, R₃ is —CO₂C₂H₅, R₄ is hydrogen, R₅ is CO₂C₂H₅, then R₆ is selected from the group consisting of hydrogen, monofluoroalkyl, and difluoroalkyl.

In yet another embodiment, the novel compounds are compounds of Formula IIA wherein:

R₂ is selected from the group consisting of alkyl and fluorinated alkyl;

R₃ is selected from the group consisting of —CO₂R₇, wherein R₇ is selected from the group consisting of hydrogen and alkyl;

R₄ is selected from the group consisting of alkyl and thio;

R₅ is selected from the group consisting of heterocyclyl, arylthioalkyl, heteroarylthioalkyl,

—CO₂R₁₄,

wherein R₁₄ is alkyl;

wherein R₃₉ is alkoxy, and

R₄₀ is haloalkyl;

—SR₄₅,

wherein R₄₅ is selected from the group consisting of hydrogen, —SR₄₆, and —CH₂R₄₇,

wherein R₄₆ is selected from the group consisting of aryl and heteroaryl, and

R₄₇ is selected from the group consisting of methylenedioxyphenyl, pyridyl, quinolinyl, naphthyl and benzodioxanyl; and

wherein R₅₀ is selected from the group consisting of alkyl and alkoxy; and

R₆ is selected from the group consisting of alkyl and fluorinated alkyl;

or a pharmaceutically acceptable salt or tautomer thereof,

provided that when R₂ is trifluoromethyl, R₃ is CO₂CH₃, R₄ is isobutyl, and R₅ is CO₂CH₃, then R₆ is selected from the group consisting of alkyl comprising at least two carbon atoms and fluorinated alkyl.

In yet another embodiment, the novel compounds of Formula IIA are selected from the compounds listed below:

Methyl 5-[(4-t-Butylphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl))-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 180);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(palmitoylthio)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 5);

Methyl 2-(Difluoromethyl)-5-(methoxycarbonylthio)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 6);

Diethyl 2,6-Bis(trifluoromethyl)-4-(trimethylsilyl)-3,5-pyridinedicarboxylate (Compound 31);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(methylthiomethylthio)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 33);

Methyl 5-(1-Bromo-2-methoxyethenyl)-4-(cyclopropylmethyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 35);

Methyl 5-(Chloroethylthio)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 44);

Methyl 4-(i-Propoxy)-5-{[3-(methoxycarbonyl)-4-(i-propoxy-)-6-(trifluoromethyl)-5-pyridyl]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 54);

Methyl 2-(Difluoromethyl)-4-cyclobutyl-5-(1-pyrrolyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 70);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(aminothionocarbonyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 77);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(dimethylamino)carbonyl]thiomethyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 79);

Methyl 2-(Difluoromethyl)-5-[(diethylphosphono)carbonyl]-4-(i-propylamino)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 85);

Dimethyl 2,6-Bis(methoxymethyl)-4-propyl-3,5-pyridinecarboxylate (Compound 92);

Methyl 5-[(Aminocarbonyl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 145);

Methyl 2-(Difluoromethyl)-5-(1-ethoxyethylthio)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 146);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(1-methoxyethylthio)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 147);

Methyl 2-(Difluoromethyl)-5-(2-fluoroethylthio)4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 148);

Methyl 5-(Acetylthio)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 149);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(2-tetrhydrofurylthio)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 150);

Methyl 2-(Difluoromethyl)-5-{[(3,5-di-t-butylphenyl)thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 151);

Methyl 2-(Difluoromethyl)-5-{[(2,4-dimethylphenyl)thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 152);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-methoxyphenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 153);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(3-methoxyphenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 154);

Methyl 2-(Difluoromethyl)-5-{[(2,4-di-t-butylphenyl)thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 155);

Methyl 5-{[(4-t-Butylphenyl)thio]carbonyl}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 156);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-isopropylphenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 157);

Methyl 2-(Difluoromethyl)-5-{[(3,5-dimethylphenyl)thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 158);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(4-methylthiophenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 159);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-(4-fluorobenzyl)-4-isopropylphenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 160);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-(4-fluorobenzyl)-4-fluorophenyl)thio]carbonyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 161);

Methyl 5-{[(4-chlorophenyl)thio]carbonyl}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 162);

Methyl 5-{[(2,5-Dichlorophenyl)thio]carbonyl}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 163);

Methyl 5-{[(2,6-Dichlorophenyl)thio]carbonyl}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 164);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(2-naphthyl)thio]carbonyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 178);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(1-naphthyl)thio]carbonyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 179);

3-Methyl 5-(3-Methoxyphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 165);

3-Methyl 5-(2-Nitrophenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 166);

3-Methyl 5-(3,5-Di-t-butylphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 167);

3-Methyl 5-(2,4-Di-t-butylphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 168);

3-Methyl 5-(4-t-Butylphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 169);

3-Methyl 5-[2-(4-Fluorobenzyl)-4-isopropylphenyl]2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 170);

3-Methyl 5-[2-(4-Fluorobenzyl)-3,4,5-(trimethoxy)phenyl] 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 171);

3-Methyl 5-(2-Methoxyphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 172);

3-Methyl 5-(4-Chlorophenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 173);

3-Methyl 5-(3,5-Dimethylphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 174);

3-Methyl 5-(2-Isopropylphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 175);

3-Methyl 5-(2,6-Dimethyl-4-nitrophenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 176);

3-Methyl 5-(2,4-Dimethylphenyl) 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridicarboxylate (Compound 177);

Methyl 5-(4-t-Butylphenyldithio)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 180);

Dimethyl 5,5′-Dithiobis[2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate] (Compound 181);

Methyl 5-{[2-(Difluoromethyl)-4-(2-methylpropyl)-3-(methoxycarbonyl)-6-(trifluoromethyl)-5-pyridyl]methylthio}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 182);

Methyl 5-{[2-(Difluoromethyl)-4-(2-methylpropyl)-3-(methoxycarbonyl)-6-(trifluoromethyl)-5-pyridyl]carbonylthio}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 183);

Methyl 5-[(3-Bromophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 184);

Methyl 5-[(4-Chlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 185);

Methyl 5-[(2,3,5,6-Tetrafluorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 186);

Methyl 5-[(3,5-Di-t-butylphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 187);

Methyl 5-[(1-Methylimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 188);

Methyl 5-[(1-Methyltetrazol-5-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 189);

Methyl 5-[(5-Nitrobenzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 190);

Methyl 5-[(4-(Trifluoromethoxy)phenyl))thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 191);

Methyl 5-[(Quinolin-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 192);

Methyl 5-[(4-Bromophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 193);

Methyl 5-[(Pentafluorophenyl)thiomethyl]-2-(difluoro-methyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 194);

Methyl 5-[(2,5-Dichlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 195);

Methyl 5-[(2,3,5,6-Tetrafluoro-4-(trifluoromethyl)phenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 196);

Methyl 5-[(4-Methylpyrimidin-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 197);

Methyl 5-[(4-Nitrophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 198);

Methyl 5-[(4-Methoxyphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 199);

Methyl 5-[(2-Chlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 200);

Methyl 5-[(2,6-Dichlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 201);

Methyl 5-[(Quinolin-8-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 202);

Methyl 5-[(Pyrimidin-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 203);

Methyl 5-[(4-(Acetylamino)phenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 204);

Methyl 5-[(Benzoxazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 205);

Methyl 5-[(4-Bromo-2-(trifluoromethoxy)phenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 206);

Methyl 5-[(3-Aminophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 207);

Methyl 5-[(2-Methoxyphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 208);

Methyl 5-[(5-Methylbenzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 209);

Methyl 5-[(Benzimidazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 210);

Methyl 5-[(3-Methoxyphenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 211);

Methyl 5-[(Benzothiazol-2-yl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 212);

Methyl 5-[(3-Chlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 213);

Methyl 5-[(3,4-Dichlorophenyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 214);

Methyl 5-[(2-Naphthyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 215);

Methyl 5-[(2-Pyridyl)thiomethyl]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 216);

Methyl 5-[(2-bromophenyl)thiomethyl]-2-(difluoro-methyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 217);

Bis(3-(carbomethoxy)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-5-pyridyl]methyl Sulfide (Compound 218);

Methyl 5-[(2-Chloro-3,4-methylenedioxyphenyl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 226);

Methyl 5-[(2-pyridyl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 233);

Methyl 5-[(2-quinolinyl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 241);

Methyl 5-[(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 245); and

Methyl 5[(6-chloro-1,3-benzodioxan-8-yl)methylthio]-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 246);

Diethyl 5,5′-(Carbonyldiimino)bis[6(difluoromethyl)-4-ethyl-2-(trifluoromethyl)-3-pyridinecarboxylate (Compound 48);

Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-{[(dimethylamino)thiono]thiomethyl}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 43);

2-(Difluoromethyl)-5-hydroxymethyl-4-phenyl-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]hydroxymethyl}pyridine;

2-(Difluoromethyl)-5-hydroxymethyl-4-phenyl-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]carbonyl}pyridine;

2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]hydroxymethyl}pyridine;

2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]carbonyl}pyridine;

2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]fluoromethyl}pyridine;

2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-([4-(trifluoromethyl)phenyl]fluoromethyl}pyridine;

2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-(2-naphthylfluoromethyl)pyridine;

2-(Difluoromethyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]mercaptomethyl}pyridine;

2-(Difluoromethyl)-5-hydroxymethyl-4-phenyl-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]mercaptomethyl}pyridine;

2-(Cyclopentyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]carbonyl)pyridine;

2-(1-Pyrrolidinyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]carbonyl}pyridine;

2-(1-Pyrrolidinyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]hydroxymethyl}pyridine; and

2-(1-Pyrrolidinyl)-5-hydroxymethyl-4-(4-fluorophenyl)-6-(trifluoromethyl)-3-{[4-(trifluoromethyl)phenyl]fluoromethyl)pyridine.

In yet another embodiment, the compound of Formula IA is Dimethyl 5,5′-dithiobis[2-difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate].

In another embodiment, the novel compounds comprise a compound of Formula IIB:

wherein:

R₂ and R₆ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; provided that at least one of R₂ and R₆ is fluorinated alkyl, chlorofluorinated alkyl or alkoxyalkyl;

R₃ is selected from the group consisting of arylcarbonyl, heteroarylcarbonyl, hydroxymethyl, arylalkoxyalkyl, trialkylsilyloxyalkyl,

—CHO,

—CO₂R₇,

wherein R₇ is selected from the group consisting of hydrogen and alkyl; and

wherein R_(15a) is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, and

R_(16a) is selected from the group consisting of alkyl, haloalkyl, alkenyl, aryl and heteroaryl;

R₄ is selected from the group consisting of hydrogen, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, alkoxy, thio, trialkylsilyl, alkylamino, and —OC(O)N(R₈)₂, wherein R₈ is aryl;

R₅ is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, aralkyl, alkoxy, aryloxy, cycloalkylthioalkyl, arylthioalkyl, heteroarylthioalkyl, alkoxyalkenyl, arylcarbonyloxyalkyl, pyrrolyl, substituted pyrrolidinyl, hydroxymethyl, arylalkoxyalkyl, and trialkylsilyloxyalkyl,

—C₂R₁₄,

wherein R₁₄ is alkyl;

wherein R_(15b) is selected from the group consisting of hydroxy, halogen, alkoxy, and alkylthio, aroyloxy, and alkylsulfonyloxy, and

R_(16b) is selected from the group consisting of alkyl, alkenyl, aryl, and heteroaryl;

wherein R₁₇ and R₁₈ are independently alkyl;

wherein R₁₉ is aryl, heteroaryl, —SR₂₀, and —OR₂₁,

wherein R₂₀ is selected from the group consisting of aryl, heteroaryl and aminoalkyl, and

R₂₁ is selected from the group consisting of aryl and heteroaryl;

wherein R₂₄ is aralkyl;

wherein R₂₈ and R₂₉ are independently alkyl;

wherein R₃₀ and R₃₁ are independently alkoxy;

—C≡C—Si(R₃₆)₃,

wherein R₃₆ is alkyl;

wherein R₃₇ is selected from the group consisting of hydrogen, alkoxy, and alkylthio, and

R₃₈ is selected from the group consisting of haloalkyl, cycloalkyl, heterocyclylalkoxy, and alkylthio;

provided that when R₃₇ is hydrogen, then R₃₈ is selected from the group consisting of haloalkyl, cycloalkyl, and heterocyclylalkoxy;

wherein R₄₂ is selected from the group consisting of hydrogen and alkyl, and

R₄₃ is substituted heteroaryl;

wherein R₄₄ is selected from the group consisting of aryl and heteroaryl;

—SR₄₅,

wherein R₄₅ is selected from the group consisting of haloalkyl, heterocyclyl, alkylthioalkyl, aminocarbonylalkyl, —SR₄₆, and —CH₂R₄₇,

wherein R₄₆ is selected from the group consisting of aryl and heteroaryl, and

R₄₇ is selected from the group consisting of methylenedioxyphenyl, pyridyl, quinolinyl, tetrahydronaphthyl and benzodioxanyl;

wherein R₄₈ is selected from the group consisting of hydrogen and alkyl, and

R₄₉ is selected from the group consisting of alkoxy and haloalkyl;

wherein R₅₀ is selected from the group consisting of alkyl, alkoxy, and heteroaryl; and

wherein R₅₁ is haloalkyl;

or a pharmaceutically acceptable salt or tautomer thereof,

provided that:

when R₂ is selected from the group consisting of difluoromethyl and trifluoromethyl, R₃ is selected from the group consisting of —CO₂H, —CO₂CH₃ and —CO₂C₂H₅, R₅ is hydrogen, and R₆ is selected from the group consisting of hydrogen and trifluoromethyl, then R₄ is selected from the group consisting of cycloalkyl, cycloalkylalkyl, heteroarylalkyl, aralkenyl, alkoxy, thio, trialkylsilyl, alkylamino, and —OC(O)N(R₈)₂, wherein R₈ is aryl; provided further that when R₂, R₃ and R₅ are as defined above, and R₄ is alkoxy, then R₆ is hydrogen;

when R₂ is selected from the group consisting of fluorinated methyl and chlorofluorinated methyl, R₃ is selected from the group consisting of hydroxymethyl and CO₂R₇, R₅ is selected from the group consisting of hydroxymethyl and CO₂R₁₄, R₆ is selected from the group consisting of fluorinated methyl and chlorofluorinated methyl, and R₇ and R₁₄ are independently alkyl, then R₄ is selected from the group consisting of thio, trialkylsilyl, and —OC(O)N(R₈)₂, wherein R₈ is aryl;

when R₂ is difluoromethyl, R₃ is —CO₂C₂H₅, R₄ is hydrogen, R₅ is —CO₂C₂H₅, then R₆ is selected from the group consisting of hydrogen, monofluoroalkyl, difluoroalkyl and alkoxyalkyl;

when R₂ is trifluoromethyl, R₃ is —CO₂R₇, R₅ is methyl, R₆ is selected from the group consisting of fluorinated methyl, fluorinated ethyl and chlorofluorinated methyl, and R₇ is selected from the group consisting of hydrogen and alkyl, then R₄ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, thio, trialkylsilyl, and —OC(O)N(R₈)₂, wherein R₈ is aryl;

when R₄ is selected from the group consisting of alkyl, cycloalkyl and cycloalkylalkyl, R₃ is —CO₂R₇, and R₇ is alkyl, then R₅ is other than arylcarbonyl, heteroarylcarbonyl or

wherein R_(16b) is alkyl when R_(15b) is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, or wherein R_(16b) is aryl or heteroaryl when R_(15b) is hydroxy;

when R₄ is selected from the group consisting of alkyl, cycloalkyl and cycloalkylalkyl, R₅ is —CO₂R₁₄, and R₁₄ is alkyl, then R₃ is other than arylcarbonyl, heteroarylcarbonyl or

wherein R_(16a) is alkyl when R_(15a) is selected from the group consisting of hydroxy, halogen, alkylthio and alkoxy, or wherein R_(16a) is aryl or heteroaryl when R_(15a) is hydroxy; and

when R₂ and R₆ are independently selected from fluorinated methyl and chlorofluorinated methyl, R₃ is CO₂R₇, R₅ is hydroxy, alkoxy or aryloxy, then R₄ is selected from the group consisting of aryl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, thio, trialkylsilyl, alkylamino, and —OC(O)N(R₈)₂, wherein R₈ is aryl; and

when R₄ is aryl and one of R₂ and R₆ is trifluoromethyl, then the other of R₂ and R₆ is difluoromethyl.

Additional Compounds

Additional novel compounds that could be used in the methods and compositions of the present invention include, but are not limited to, the compounds:

and those compounds listed in Tables 9, 10, 11 and 12 below. These compounds could be prepared by appropriate modification of the synthetic schemes previously referenced in this application.

TABLE 9

R¹ R² X Y Z Cl H H OH H iPr H H OH H F H H OH H CF₃ H H OH H Cl H O O H iPr H O O H F H O O H CF₃ H O O H Cl H F H H iPr H F H H F H F H H CF₃ H F H H Cl H H OH CH₃ iPr H H OH CH₃ F H H OH CH₃ CF₃ H H OH CH₃ Cl H O O CH₃ iPr H O O CH₃ F H O O CH₃ CF₃ H O O CH₃ Cl H F H CH₃ iPr H F H CH₃ F H F H CH₃ CF₃ H F H CH₃ Cl H H OH C₂H₅ iPr H H OH C₂H₅ F H H OH C₂H₅ CF₃ H H OH C₂H₅ Cl H O O C₂H₅ iPr H O O C₂H₅ F H O O C₂H₅ CF₃ H O O C₂H₅ Cl H F H C₂H₅ iPr H F H C₂H₅ F H F H C₂H₅ CF₃ H F H C₂H₅ Cl H H OH iBu iPr H H OH iBu F H H OH iBu CF₃ H H OH iBu Cl H O O iBu iPr H O O iBu F H O O iBu CF₃ H O O iBu Cl H F H iBu iPr H F H iBu F H F H iBu CF₃ H F H iBu Cl H H OH CF₃ iPr H H OH CF₃ F H H OH CF₃ CF₃ H H OH CF₃ Cl H O O CF₃ iPr H O O CF₃ F H O O CF₃ CF₃ H O O CF₃ Cl H F H CF₃ iPr H F H CF₃ F H F H CF₃ CF₃ H F H CF₃

TABLE 10

R¹ R² X Y Z Cl H H OH H iPr H H OH H F H H OH H CF₃ H H OH H Cl H O O H iPr H O O H F H O O H CF₃ H O O H Cl H F H H iPr H F H H F H F H H CF₃ H F H H Cl H H OH CH₃ iPr H H OH CH₃ F H H OH CH₃ CF₃ H H OH CH₃ Cl H O O CH₃ iPr H O O CH₃ F H O O CH₃ CF₃ H O O CH₃ Cl H F H CH₃ iPr H F H CH₃ F H F H CH₃ CF₃ H F H CH₃ Cl H H OH C₂H₅ iPr H H OH C₂H₅ F H H OH C₂H₅ CF₃ H H OH C₂H₅ Cl H O O C₂H₅ iPr H O O C₂H₅ F H O O C₂H₅ CF₃ H O O C₂H₅ Cl H F H C₂H₅ iPr H F H C₂H₅ F H F H C₂H₅ CF₃ H F H C₂H₅ Cl H H OH iBu iPr H H OH iBu F H H OH iBu CF₃ H H OH iBu Cl H O O iBu iPr H O O iBu F H O O iBu CF₃ H O O iBu Cl H F H iBu iPr H F H iBu F H F H iBu CF₃ H F H iBu Cl H H OH CF₃ iPr H H OH CF₃ F H H OH CF₃ CF₃ H H OH CF₃ Cl H O O CF₃ iPr H O O CF₃ F H O O CF₃ CF₃ H O O CF₃ Cl H F H CF₃ iPr H F H CF₃ F H F H CF₃ CF₃ H F H CF₃

TABLE 11

R¹ R² X Y Z R³ Cl H H OH H CH₃ iPr H H OH H CH₃ F H H OH H CH₃ CF₃ H H OH H CH₃ Cl H O O H CH₃ iPr H O O H CH₃ F H O O H CH₃ CF₃ H O O H CH₃ Cl H F H H CH₃ iPr H F H H CH₃ F H F H H CH₃ CF₃ H F H H CH₃ Cl H H OH CH₃ CH₃ iPr H H OH CH₃ CH₃ F H H OH CH₃ CH₃ CF₃ H H OH CH₃ CH₃ Cl H O O CH₃ CH₃ iPr H O O CH₃ CH₃ F H O O CH₃ CH₃ CF₃ H O O CH₃ CH₃ Cl H F H CH₃ CH₃ iPr H F H CH₃ CH₃ F H F H CH₃ CH₃ CF₃ H F H CH₃ CH₃ Cl H H OH C₂H₅ CH₃ iPr H H OH C₂H₅ CH₃ F H H OH C₂H₅ CH₃ CF₃ H H OH C₂H₅ CH₃ Cl H O O C₂H₅ CH₃ iPr H O O C₂H₅ CH₃ F H O O C₂H₅ CH₃ CF₃ H O O C₂H₅ CH₃ Cl H F H C₂H₅ CH₃ iPr H F H C₂H₅ CH₃ F H F H C₂H₅ CH₃ CF₃ H F H C₂H₅ CH₃ iPr H H OH iBu CH₃ F H H OH iBu CH₃ CF₃ H H OH iBu CH₃ Cl H O O iBu CH₃ iPr H O O iBu CH₃ F H O O iBu CH₃ CF₃ H O O iBu CH₃ Cl H F H iBu CH₃ iPr H F H iBu CH₃ F H F H iBu CH₃ CF₃ H F H iBu CH₃ Cl H H OH CF₃ CH₃ iPr H H OH CF₃ CH₃ F H H OH CF₃ CH₃ CF₃ H H OH CF₃ CH₃ Cl H O O CF₃ CH₃ iPr H O O CF₃ CH₃ F H O O CF₃ CH₃ CF₃ H O O CF₃ CH₃ Cl H F H CF₃ CH₃ iPr H F H CF₃ CH₃ F H F H CF₃ CH₃ CF₃ H F H CF₃ CH₃ Cl H H OH H Ph iPr H H OH H Ph F H H OH H Ph CF₃ H H OH H Ph Cl H O O H Ph iPr H O O H Ph F H O O H Ph CF₃ H O O H Ph Cl H F H H Ph iPr H F H H Ph F H F H H Ph CF₃ H F H H Ph Cl H H OH CH₃ Ph iPr H H OH CH₃ Ph F H H OH CH₃ Ph CF₃ H H OH CH₃ Ph Cl H O O CH₃ Ph iPr H O O CH₃ Ph F H O O CH₃ Ph CF₃ H O O CH₃ Ph Cl H F H CH₃ Ph iPr H F H CH₃ Ph F H F H CH₃ Ph CF₃ H F H CH₃ Ph Cl H H OH C₂H₅ Ph iPr H H OH C₂H₅ Ph F H H OH C₂H₅ Ph CF₃ H H OH C₂H₅ Ph Cl H O O C₂H₅ Ph iPr H O O C₂H₅ Ph F H O O C₂H₅ Ph CF, H O O C₂H₅ Ph Cl H F H C₂H₅ Ph iPr H F H C₂H₅ Ph F H F H C₂H₅ Ph CF₃ H F H C₂H₅ Ph iPr H H OH iBu Ph F H H OH iBu Ph OF3 H H OH iBu Ph Cl H O O iBu Ph iPr H O O iBu Ph F H O O iBu Ph CF₃ H O O iBu Ph Cl H F H iBu Ph iPr H F H iBu Ph F H F H iBu Ph CF₃ H F H iBu Ph Cl H H OH H CF₃ iPr H H OH H CF₃ F H H OH H CF₃ CF₃ H H OH H CF₃ Cl H O O H CF₃ iPr H O O H CF₃ F H O O H CF₃ CF₃ H O O H CF₃ Cl H F H H CF₃ iPr H F H H CF₃ F H F H H CF₃ CF₃ H F H H CF₃

TABLE 12

R¹ R² X Y Z R³ Cl H H OH H CH₃ iPr H H OH H CH₃ F H H OH H CH₃ CF₃ H H OH H CH₃ CI H O O H CH₃ iPr H O O H CH₃ F H O O H CH₃ CF₃ H O O H CH₃ Cl H F H H CH₃ iPr H F H H CH₃ F H F H H CH₃ CF₃ H F H H CH₃ CI H H OH CH₃ CH₃ iPr H H OH CH₃ CH₃ F H H OH CH₃ CH₃ CF₃ H H OH CH₃ CH₃ Cl H O O CH₃ CH₃ iPr H O O CH₃ CH₃ F H O O CH₃ CH₃ CF₃ H O O CH₃ CH₃ Cl H F H CH₃ CH₃ iPr H F H CH₃ CH₃ F H F H CH₃ CH₃ CF₃ H F H CH₃ CH₃ Cl H H OH C₂H₅ CH₃ iPr H H OH C₂H₅ CH₃ F H H OH C₂H₅ CH₃ CF₃ H H OH C₂H₅ CH₃ Cl H O O C₂H₅ CH₃ iPr H O O C₂H₅ CH₃ F H O O C₂H₅ CH₃ CF₃ H O O C₂H₅ CH₃ Cl H F H C₂H₅ CH₃ iPr H F H C₂H₅ CH₃ F H F H C₂H₅ CH₃ CF₃ H F H C₂H₅ CH₃ iPr H H OH iBu CH₃ F H H OH iBu CH₃ CF₃ H H OH iBu CH₃ Cl H O O iBu CH₃ iPr H O O iBu CH₃ F H O O iBu CH₃ CF₃ H O O iBu CH₃ Cl H F H iBu CH₃ iPr H F H iBu CH₃ F H F H iBu CH₃ CF₃ H F H iBu CH₃ Cl H H OH CF₃ CH₃ iPr H H OH CF₃ CH₃ F H H OH CF₃ CH₃ CF₃ H H OH CF₃ CH₃ Cl H O O CF₃ CH₃ iPr H O O CF₃ CH₃ F H O O CF₃ CH₃ CF₃ H O O CF₃ CH₃ Cl H F H CF₃ CH₃ iPr H F H CF₃ CH₃ F H F H CF₃ CH₃ CF₃ H F H CF₃ CH₃ Cl H H OH H Ph iPr H H OH H Ph F H H OH H Ph CF₃ H H OH H Ph Cl H O O H Ph iPr H O O H Ph F H O O H Ph CF₃ H O O H Ph Cl H F H H Ph iPr H F H H Ph F H F H H Ph CF₃ H F H H Ph Cl H H OH CH₃ Ph iPr H H OH CH₃ Ph F H H OH CH₃ Ph CF₃ H H OH CH₃ Ph Cl H O O CH₃ Ph iPr H O O CH₃ Ph F H O O CH₃ Ph CF₃ H O O CH₃ Ph Cl H F H CH₃ Ph iPr H F H CH₃ Ph F H F H CH₃ Ph CF₃ H F H CH₃ Ph Cl H H OH C₂H₅ Ph iPr H H OH C₂H₅ Ph F H H OH C₂H₅ Ph CF₃ H H OH C₂H₅ Ph Cl H O O C₂H₅ Ph iPr H O O C₂H₅ Ph F H O O C₂H₅ Ph CF₃ H O O C₂H₅ Ph Cl H F H C₂H₅ Ph iPr H F H C₂H₅ Ph F H F H C₂H₅ Ph CF₃ H F H C₂H₅ Ph iPr H H OH iBu Ph F H H OH iBu Ph CF₃ H H OH iBu Ph Cl H O O iBu Ph iPr H O O iBu Ph F H O O iBu Ph CF₃ H O O iBu Ph Cl H F H iBu Ph iPr H F H iBu Ph F H F H iBu Ph CF₃ H F H iBu Ph Cl H H OH H CF₃ iPr H H OH H CF₃ F H H OH H CF₃ CF₃ H H OH H CF₃ Cl H O O H CF₃ iPr H O O H CF₃ F H O O H CF₃ CF₃ H O O H CF₃ Cl H F H H CF₃ iPr H F H H CF₃ F H F H H CF₃ CF₃ H F H H CF₃

Pharmaceutical Compositions

Also embraced within this invention is a class of pharmaceutical compositions comprising the active compounds of Formulae I, IA, IB and/or Formulae IIA or IIB in association with one or more non-toxic, pharmaceutically-acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as “carrier” materials) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and compositions may, for example, be administered orally, intravascularly, intraperitoneally, subcutaneously, intramuscularly or topically.

The phrase “co-therapy” (or combination-therapy), in defining use of a compound of the present invention and another pharmaceutical agent, is intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent. The compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in co-therapy with one or more cardiovascular agents, such as compounds that lower serum cholesterol concentrations including inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors such as the statins (atorvastatin, cerivastatin, pravastatin, simvastatin, fluvastatin and lovastatin), inhibitors of squalene synthase, oxido squalene cyclase or inhibitors of other enzymes involved with cholesterol biosynthesis; inhibitors of the ileal bile acid transport protein (IBAT), cholesterol absorption antagonists, ACAT inhibitors, bile acid sequestrants such as Cholestyramine and Cholestagel, fibrates such as Gemfibrozil, niacins such as Niaspan, and omega-3 fatty acids such as Omacor. Compounds of the present invention can also be used in co-therapy with cardiovascular drugs that reduce hypertension such as Enalopril and Captopril, or with anti-diabetes drugs such as troglitazone, or with antithrombotic agents such as aspirin, warfarin, and glycoprotein IIbIIIa antagonists such as Reopro, Xemilofiban and Orbofiban. The compounds of this invention can also be used in co-therapy with agents which lower serum triglyceride concentrations, including inhibitors of cholesterol biosynthesis such as HMG-CoA reductase inhibitors such as the statins (atorvastatin), fibrates such as Gemfibrozil, niacins such as Niaspan, and omega-3 fatty acids such as Omacor.

The phrase “therapeutically-effective” is intended to qualify the amount of each agent which will achieve the goal of improvement in disease severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.

For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets or capsules. The active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable carrier.

The amount of therapeutically active compounds which are administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention depends on a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely. Patients undergoing treatment with the compounds and/or compositions disclosed herein can be routinely monitored by conventional methods to determine the effectiveness of therapy. Continuous analysis of the data obtained permits modification of the treatment regimen during treatment so that optimal amounts of the compounds and/or compositions of this invention are administered, and so that the duration of treatment can be determined as well. Thus, the treatment regimen/dosing schedule can be rationally modified over the course of treatment so as to achieve the lowest doses of each of the compounds and/or compositions of this invention which together result in satisfactory anti-lipidemic effectiveness, and so that administration of these compounds is continued only so long as is necessary to successfully treat the patient.

The pharmaceutical compositions may contain active ingredients in the range of about 0.1 to 2000 mg, and preferably in the range of about 0.5 to 500 mg. A daily dose of about 0.01 to 100 mg/kg body weight, and preferably between about 0.5 and about 20 mg/kg body weight, may be appropriate. The daily dose can be administered in one to four doses per day.

The compounds may be formulated in topical ointment or cream, or as a suppository, containing the active ingredients in a total amount of, for example, 0.075 to 30% w/w, preferably 0.2 to 20% w/w and most preferably 0.4 to 15% w/w. When formulated in an ointment, the active ingredients may be employed with either paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol and mixtures thereof. The topical formulation may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogs. The compounds of this invention can also be administered by a transdermal device. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety. In either case, the active agent is delivered continuously from the reservoir or microcapsules through a membrane into the active agent permeable adhesive, which is in contact with the skin or mucosa of the recipient. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of microcapsules, the encapsulating agent may also function as the membrane.

The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make-up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate, among others.

The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations is very low. Thus, the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters may be used. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredients are dissolved or suspended in suitable carrier, especially an aqueous solvent for the active ingredients. The antiinflammatory active ingredients are preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly about 1.5% w/w.

For therapeutic purposes, the active compounds of this combination invention are ordinarily combined with one or more adjuvants appropriate to the indicated route of administration. If administered per os, the compounds may be admixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropylmethyl cellulose. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.

Additional Substituted Pyridines

The present invention further includes a group of substituted pyridines which exhibit percentage transfers in excess of 100% and are useful (i) in examining the structural requirements of the active site of the CTEP molecule, (ii) as control pyridines in the study of the mechanism for inhibiting the activity of CETP, and (ii) in the design of substituted pyridines which are effective CTEP inhibitors. Accordingly, they are useful in studying the prevention and treatment of dyslipidemia (hypoalphalipoproteinaemia), hyperlipoproteinaemia (chylomicronemia and hyperapobetalipoproteinaemia), peripheral vascular disease, hypercholesterolemia, atherosclerosis, coronary artery disease and other CETP-mediated disorders. These substituted pyridines include those compounds listed in Table 13 below:

TABLE 13 (T-8)

CP R₂ R₃ R₄ R₅ R₆ 300 OCH₃ H H CO₂H H 301 CF₂H CO₂CH₃ i-Bu NHC(O)CH₂Br CF₃ 302 CF₃ H CF₃ CO₂C₂H₅ CH₂CO₂C₂H₅ 303 CF₂H CO₂CH₃ i-Pr C(O)N(CH₃)OCH₃ CF₃ 304 NH₂ CO₂H H H H 305 CH₃ CO₂C₂H₅ H CO₂C₂H₅ CH₃ 306 CF₃ CO₂C₂H₅ Et CN CF₂H 307 CF₃ CO₂CH₃ O-i-Pr S(O)Ph CF₃ 308 CH₂CO₂C₂H₅ CO₂C₂H₅ H H H 309 CF₃ CO₂CH₃ OH SPh CF₃ 310 CF₂C CO₂CH₃ 1- CO₂C₂H₅ CF₃ azyridinyl 311 CF₃ CO₂CH₃ OC(O)-(4- H CF₃ CF₃—Ph) 312 CO₂H H H H CO₂H 313 CF₃ CO₂CH₃ i-Bu CO₂CH₃ CH₃ 314 CF₂H CO₂C₂H₅ H CO₂C₂H₅ CF₃ 315 CF₃ CO₂C₂H₅ OCH₂CH═CH₂ H CF₃ 316 CF₂H CON(CH₃)₂ i-Bu CO₂CH₃ CF₃ 317 CF₂H CO₂H CH═C(CH₃)₂ CN CF₃ 318 CF₃ CO₂CH₃ OC(O)-Pr H CF₃ 319 CF₃ CO₂CH₃ O-(4-Cl—Ph) H CF₃ 320 CF₂H CO₂CH₃ NH-i-Pr C(O)-1- CF₃ pyrazolyl 321 CF₃ CO₂C₂H₅ OH CH₃ H 322 CH₃ CO₂C₂H₅ H C(O)NHCH₂-(4- CH₃ Cl—Ph) 323 CF₂H CO₂CH₃ Pr C(O)NH(CH_(2l )) ₂Cl CF₃ 324 CF₃ CO₂CH₃ OC(O)-t-Bu H CF₃ 325 CF₂H CO₂H CH═C(CH₃)₂ CO₂CH₃ CF₃ 326 CF₂H CO₂CH₃ N═S(CH₃)₂ CO₂C₂H₅ CF₃ 327 OH CO₂H H H CH₃ 328 CF₂H CO₂CH₃ Pr C(O)N(CH₃)OCH₃ CF₃ 329 CF₃ CO₂C₂H₅ OH H H 330 CF₂H CO₂CH₃ i-Bu NHC(O)CH₃ CF₃ 331 H CO₂CH₃ H H OCH₃ 332 CF₃ CO₂H OH CH₃ CF₃ 333 CF₂H CO₂CH₃ i-Bu C(O)NH(CH₂)₃OH CF₃ 334 CH₃ CO₂CH₃ CF₃ H CH₃ 335 CF₃ CO₂CH₃ OCH₃ NHCO₂CH₃ CF₃ 336 CF₂H CO₂CH₃ CH₂-c-Pr 2-oxazolinyl CF₃ 337 CF₃ CO₂CH₃ O(CO)- H CF₃ (pentafluoro- phenyl) 338 CF₂H CO₂CH₃ i-Bu C(SCH₃)═NCH₂Ph CF₃ 339 CH₃ CO₂C₂H₅ O-i-Pr CO₂C₂H₅ CH₃ 340 CF₂H CO₂H CH₂SCH₃ CO₂C₂H₅ CF₃ 342 CF₃ CO₂CH₃ i-Bu CO₂CH₃ CH(1-morpholinyl)₂ 342 CF₂H CO₂CH₃ i-Pr C(O)NH(CH₂)₂OH CF₃ 343 CF₂H CONHCH₃ i-Pr CO₂C₂H₅ CF₃ 344 CF₂H CO₂CH₃ CH₂S⁺(CH₃)₂ CO₂C₂H₅ CF₃ BF₄ ⁻ 345 CF₃ Si(CH₃)₃ OCH₃ CO₂CH₃ CF₃ 346 CF₂H CO₂CH₃ i-Pr C(O)N(CH₃)₂ CF₃ 347 CH₃ CO₂CH₃ i-Bu CO₂CH₃ CH₂Cl 348 CH₃ CO₂C₂H₅ CO₂C₂H₅ OS(O)₂-(4- CH₃ CH₃Ph) 349 CF₃ CO₂H H H CF₃ 350 CF₂H CO₂CH₃ i-Bu H CF₃

Definitions and Abbreviations

The use of generic terms and abbreviations in the description of the compounds are herein defined for clarity.

The term “alkyl”, either alone or within other terms such as “haloalkyl”, “cyanoalkyl” and “alkylthio”, embraces substituted or unsubstituted linear or branched radicals having one to about 10 carbon atoms. More preferred alkyl radicals are “lower alkyl” radicals having one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and the like. The term “higher alkyl” denotes linear or branched radicals having eleven to about twenty carbon atoms. Examples of such radicals include undecyl, dodecyl, tridecyl, tetradecyl, and pentadecyl.

The term “alkenyl”, either alone or within other terms such as “haloalkenyl” and “alkenylthio”, embraces substituted or unsubstituted linear or branched radicals having one to about 10 carbon atoms and having one or more double bonds. More preferred alkenyl radicals are “lower alkenyl” radicals having one to about six carbon atoms. Examples of such radicals include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like. The term “higher alkenyl” denotes linear or branched radicals having from 11 to about 20 carbon atoms and having one or more double bonds. Examples of such radicals include undecenyl, dodecenyl, tridecenyl, tetradecenyl, and pentadecenyl. Preferably, the unsaturation is remote from the moiety attaching the alkenyl group to the pyridine ring.

The term “alkynyl”, either alone or within other terms such as “haloalkynyl” and “alkynylthio”, embraces substituted or unsubstituted linear or branched radicals having one to about 10 carbon atoms and having one or more triple bonds. More preferred alkynyl radicals are “lower alkynyl” radicals having one to about six carbon atoms. Examples of such radicals include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. The term “higher alkynyl” denotes linear or branched radicals having from 11 to about 20 carbon atoms having one or more triple bonds. Examples of such radicals include undecynyl, dodecynyl, tridecynyl, tetradecynyl, and pentadecynyl. Preferably, the unsaturation is remote from the moiety attaching the alkynyl group to the pyridine ring.

The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term “aryl” embraces aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane, anthryl and biphenyl. Said “aryl” group can be substituted or unsubstituted.

The term “heterocyclyl” embraces saturated or partially saturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Partially saturated heterocyclyl radicals have at least one double bond, but less than the maximum number of double bonds possible for the heterocyclyl ring. Examples of saturated heterocyclic radicals include saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g. azyrindinyl, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 oxygen atoms [e.g. oxiranyl, oxolanyl, dioxolanyl, dioxanyl, etc.]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 4 sulfur atoms [e.g. thiolanyl, dithiolanyl, dithianyl, etc.]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. oxazolidinyl, morpholinyl, etc.]; saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl, etc.]; and saturated 3 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 oxygen atoms [e.g., oxathiolanyl, etc.]. Examples of partially saturated heterocyclyl radicals include imidazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, dihydrothiophene, dihydropyran and dihydrofuran. Heterocyclic radicals also encompass unsaturated or partially saturated condensed heterocyclic radicals such as benzodioxanyl. Heterocyclyl radicals further can be unsubstituted or substituted with one or more groups including, for example, alkyl, halo, alkoxy, nitro, trifluoromethoxy, cycloalkyl, haloalkyl, alkylthio, alkylidene, acylamino, aryloxy, arylalkoxy, and oxo.

The term “heteroaryl” embraces unsaturated heteroatom-containing ring-shaped radicals, where the heteroatoms may be selected from nitrogen, sulfur and oxygen. Heteroaryl radicals have the maximum number of double bonds possible for the heterocyclyl ring. Examples of heteroaryl radicals include unsaturated 5 to 6 membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, triazolyl, tetrazolyl, etc.; unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl and benzotriazolyl, etc.; unsaturated 3 to 6-membered heteromonocyclic groups containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5 to 6-membered heteromonocyclic groups containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to 6-membered heteromonocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl and isoxazolyl, etc.; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. benzoxazolyl, benzoxadiazolyl, etc.]; unsaturated 5 to 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, isothiazolyl, thiadiazolyl [e.g., 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.] etc.; unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazolyl, etc.] and the like. The term also embraces radicals where heterocyclic radicals are fused with aryl radicals. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like. Said “heterocyclyl” group may have 1 to 3 substituents such as, for example, lower alkyl, lower alkoxy, halo, hydroxy, oxo, amino and lower alkylamino. Preferred heterocyclic radicals include five to ten membered fused or unfused radicals. More preferred examples of heteroaryl radicals include pyridyl, thienyl, thiazolyl, oxazolyl, furyl, and pyrazinyl. Heteroaryl can be unsubstituted or substituted with one or more groups selected from, for example, alkyl, halo, alkoxy, nitro, trifluoro-methoxy, cycloalkyl, haloalkyl, alkylthio, alkylidene, acylamino, aryloxy, arylalkoxy, and oxo.

The term “cycloalkyl” embraces substituted or unsubstituted radicals having three to ten carbon atoms. More preferred cycloalkyl radicals are “lower cycloalkyl” radicals having three to seven carbon atoms. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term “cycloalkylalkyl” embraces cycloalkyl-substituted alkyl radicals. Preferable cycloalkylalkyl radicals are “lower cycloalkylalkyl” radicals having cycloalkyl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include cyclopropylmethyl and cyclohexylhexyl. Also preferred cycloalkylalkyl radicals are “higher cycloalkylalkyl” radicals having cycloalkyl radicals attached to alkyl radicals having seven to fifteen carbon atoms. Examples of such radicals include cyclohexyldodecyl.

The term “cycloalkenyl” embraces radicals having three to ten carbon atoms and one or more carbon-carbon double bonds. More preferred cycloalkenyl radicals are “lower cycloalkenyl” radicals having three to seven carbon atoms. Examples include radicals such as cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl. Said “aryl” group may have 1 to 3 substituents such as, for example, lower alkyl, alkoxy, halo, hydroxy, oxo, amino and lower alkylamino.

The term “aralkyl” embraces aryl-substituted alkyl radicals. Preferable aralkyl radicals are “lower aralkyl” radicals having aryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include benzyl, diphenylmethyl, triphenylmethyl, phenylethyl and diphenylethyl. Also preferred aralkyl radicals are “higher aralkyl” radicals having aryl radicals attached to alkyl radicals having seven to fifteen carbon atoms. Examples of such radicals include phenyloctyl and phenylundecyl. The aryl in said aralkyl may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The terms benzyl and phenylmethyl are used herein interchangeably.

The term “heteroaralkyl” embraces heteroaryl-substituted alkyl radicals. Preferable heteroaralkyl radicals are “lower heteroaralkyl” radicals having heteroaryl radicals attached to alkyl radicals having one to six carbon atoms. Examples of such radicals include —CH(OH)-2-furyl; —CH(OH)-2-thienyl; —CH(OCH₃)-2-thienyl; and —CH(OCH₃)-(5-isothiazolyl). Also preferred heteroaralkyl radicals are “higher heteroaralkyl” radicals having heteroaryl radicals attached to alkyl radicals having seven to fifteen carbon atoms. The heteroaryl in said heteroaralkyl may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The term “heterocyclylalkyl” embraces heterocyclyl-substituted alkyl radicals. Preferable heterocyclylalkyl radicals are “lower heterocyclylalkyl” radicals having heterocyclyl radicals attached to alkyl radicals having one to six carbon atoms. An examples of such radicals is —CH₂-(2-thiazolinyl). Also preferred heterocyclylalkyl radicals are “higher heterocyclylalkyl” radicals having heterocyclyl radicals attached to alkyl radicals having seven to fifteen carbon atoms. The heterocyclyl radical in said heterocyclylalkyl may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The term “aralkenyl” embraces aryl-substituted alkenyl radicals. Preferable aralkenyl radicals are “lower aralkenyl” radicals having aryl radicals attached to alkenyl radicals having one to six carbon atoms. Examples of such radicals include —CH═C(CH₃)Ph. Also preferred aralkenyl radicals are “higher aralkenyl” radicals having aryl radicals attached to alkenyl radicals having seven to fifteen carbon atoms. The aryl in said aralkenyl may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The term “alkoxy” embraces linear or branched oxy-containing radicals each having alkyl portions of one to about ten carbon atoms, such as methoxy radical. More preferred alkoxy radicals are “lower alkoxy” radicals having one to six carbon atoms. Examples of such radicals include methoxy, ethoxy, propoxy, iso-propoxy, butoxy and tert-butoxy. The “alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkoxy” radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term “aryloxy” embraces aryl radicals, as defined above, attached to an oxygen atom. Examples of such radicals include phenoxy. The aryl in said aryloxy may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy. The term “aralkoxy” embraces oxy-containing aralkyl radicals attached through an oxygen atom to other radicals. More preferred aralkoxy radicals are “lower aralkoxy” radicals having phenyl radicals attached to lower alkoxy radical as described above. The aryl in said aralkoxy radicals may be additionally substituted with, for example halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The term “aryloxyalkyl” embraces aryloxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenoxymethyl. The aryl in said aryloxyalkyl may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The term “alkoxyalkyl” embraces alkoxy radicals, as defined above, attached to an alkyl group. Examples of such radicals include methoxymethyl. Also preferred alkoxyalkyl radicals are “higher alkoxyalkyl” radicals having seven to fifteen carbon atoms. An example of “higher alkoxyalkyl” is undecyloxymethyl.

The term “alkoxyalkenyl” embraces linear or branched alkenyl radicals having one or more alkoxy radicals attached to the alkenyl radical, that is, to form monoalkoxyalkenyl and dialkoxyalkenyl radicals. Preferred alkoxyalkenyl radicals are “lower alkoxyalkenyl” radicals having alkoxy radicals of six to fifteen carbon atoms. An examples of such radicals is —CH═CHOCH₃. The “alkenyl” and/or “alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide “haloalkenyl” and/or “haloalkoxy” radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term “aralkoxy” embraces alkoxy radicals having one or more aryl radicals attached to the alkoxy radical, that is, to form monoaralkoxy and diaralkoxy radicals. Preferred aralkoxy radicals are “lower aralkoxy” radicals having alkoxy radicals of one to ten carbon atoms. Examples of such radicals include phenylmethoxy. The “aryl” and “alkoxy” radicals may be further substituted with, for example, halogen, alkyl, haloalkyl, alkoxy, nitro, carboxy, carbalkoxy, alkylthio, alkylamino, dialkylamino, and amino. Examples of such radicals include, for example, methyl, chloro, trifluoromethyl, methoxy, —CO₂H, —CO₂C₂H₅, methylthio, methylamino and dimethylamino.

The term “heteroaralkoxy” embraces alkoxy radicals having one or more heteroaryl radicals attached to the alkoxy radical, that is, to form monoheteroaralkoxy and diheteroaralkoxy radicals. Preferred heteroaralkoxy radicals are “lower heteroaralkoxy” radicals having alkoxy radicals of one to ten carbon atoms. Examples of such radicals include oxaranylmethoxy and 2-pyridylmethoxy. The “heteroaryl” and “alkoxy” radicals may be further substituted with, for example, halogen, alkyl, haloalkyl, alkoxy, nitro, carboxy, carbalkoxy, alkylthio, alkylamino, dialkylamino, and amino. Examples of such radicals include, for example, methyl, chloro, trifluoromethyl, methoxy, —CO₂H, —CO₂C₂H₅, methylthio, methylamino and dimethylamino.

The term “carbonyl” embraces the —C(O)— radical found in such compounds as aldehydes and ketones.

The term “alkoxycarbonyl” embraces a carbonyl group, as defined above, having an attached alkoxy radical. Examples of such radicals include methoxycarbonyl and ethoxycarbonyl. The “alkoxy” radicals may be further substituted with, for example, halogen and cyano. Examples of such radicals include fluoroethoxycarbonyl and cyanomethoxycarbonyl.

The term “arylcarbonyloxy” embraces a carbonyl radical attached through an oxygen atom to other radicals and additionally having an aryl radical attached to the carbonyl group. More preferred arylcarbonyloxy radicals are “lower arylcarbonyloxy” radicals having phenyl radicals attached to the carbonyl radical as described above, such as benzoyloxy. The aryl in said arylcarbonyloxy radicals may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The term “arylcarbonyloxyalkyl” embraces an arylcarbonyloxy radical, as defined above, attached to attached an alkyl radical. More preferred arylcarbonyloxyalkyl radicals are “lower arylcarbonyloxyalkyl” radicals wherein the aryl portion of the arylcarbonyloxyalkyl radical comprises one or more phenyl radicals attached to the carbonyl as described above, such as benzoyloxymethyl. The aryl in said arylcarbonyloxy radicals may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The term “thio” embraces radicals containing a divalent sulfur. An example of a thio radical is the sulfhydryl (or —SH) radical.

The term “alkylthio” embraces radicals containing a linear or branched alkyl radical, of one to ten carbon atoms, attached to a divalent sulfur atom. More preferred alkylthio radicals are “lower alkylthio” radicals having one to six carbon atoms. Examples of “lower alkylthio” include methylthio (—S—CH₃) and ethylthio (—S—CH₂CH₃) Also preferred alkylthio radicals are “higher alkylthio” radicals having seven to fifteen carbon atoms. An example of “higher alkylthio” is dodecylthio.

The term “cycloalkylthio” embraces radicals containing a cyclic alkyl radical, of three to ten carbon atoms, attached to a divalent sulfur atom. More preferred cycloalkylthio radicals are “lower cycloalkylthio” radicals having three to six carbon atoms. An example of “lower cycloalkylthio” is cyclobutylthio. Also preferred cycloalkylthio radicals are “higher cycloalkylthio” radicals having seven to fifteen carbon atoms. An example of “higher cycloalkylthio” is cyclooctylthio.

The term “arylthio” embraces aryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include phenylthio. The aryl in said arylthio may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The term “heteroarylthio” embraces heteroaryl radicals, as defined above, attached to an sulfur atom. Examples of such radicals include pyridylthio. The heteroaryl in said heteroarylthio may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The term “alkylthioalkyl” embraces alkylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include methylthiomethyl and ethylthioethyl. Also preferred alkylthioalkyl radicals are “higher alkylthioalkyl” radicals having seven to fifteen carbon atoms. An example of “higher alkylthioalkyl” is undecylthiomethyl.

The term “arylthioalkyl” embraces arylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include phenylthiomethyl. The aryl in said arylthioalkyl may be additionally substituted with halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The term “heteroarylthioalkyl” embraces heteroarylthio radicals, as defined above, attached to an alkyl group. Examples of such radicals include pyrimidinylthiomethyl. The heteroaryl in said heteroarylthioalkyl may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The term “halo” or “halogen” means halogens such as fluorine, chlorine, bromine or iodine atoms. The term “haloalkyl” embraces radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have either a bromo, chloro or a fluoro atom within the radical. Dihalo radicals may have two or more of the same halo atoms or a combination of different halo radicals and polyhaloalkyl radicals may have more than two of the same halo atoms or a combination of different halo radicals. More preferred haloalkyl radicals are “lower haloalkyl” radicals having one to about six carbon atoms. Examples of such haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The term “chlorinated methyl” means a methyl group having one or more chlorine atoms bonded thereto, including a alkyl radical wherein all the hydrogen atoms are replaced by chlorine. The term “fluorinated alkyl” means an alkyl group having one or more fluorine atoms bonded thereto, including a methyl radical wherein all the hydrogen atoms are replaced by fluorine. Fluorinated methyl is the preferred fluorinated alkyl. The term “chlorofluorinated methyl” means a methyl group having a chloro atom and one or two fluorine atoms bonded thereto, including a methyl radical wherein all the hydrogen atoms are replaced by a chlorine atom and two fluorine atoms.

The term “amido” or “aminocarbonyl” embraces amino radicals attached to a carbonyl radicals. The amino radical in said amido radical may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The term “alkylamino” embraces an alkyl radical, as defined above, attached to an amino group. Examples of such alkylamino radicals include methylamino and ethylamino. The alkyl radical in said alkylamino radical may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The term “trialkylsilyl” embraces silyl radicals tri-substituted with alkyl radicals. Examples of such trialkylsilyl radicals include trimethylsilyl and triethylsilyl. The alkyl radical in said trialkylsilyl radical may be additionally substituted with, for example, halo, alkyl, alkoxy, halkoalkyl and haloalkoxy.

The terms “cis” and “trans” denote a form of geometric isomerism in which two carbon atoms connected by a double bond will each have a hydrogen atom on the same side of the double bond (“cis”) or on opposite sides of the double bond (“trans”).

In addition to those substitutions described above, the substituents of the substituted alkyl, alkenyl, alkynyl, aryl, and heteroaryl groups and other moieties described above include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, nitrogen, oxygen, sulfur, haloalkyl such as trifluoromethyl, lower alkoxy such as methoxy, ethoxy or butoxy, lower haloalkoxy, hydroxy, halogen such as chloro or fluoro, nitro, amino, and keto.

As used herein, “Ph” means phenyl; “Me” means methyl”; “Et” means ethyl; “Ethylidine” means the group CH₃CH═; “R” means alkyl unless otherwise defined; “Pr” means propyl; “i-Pr” means iso-propyl; “i-propoxy” means isopropoxy; “c-Pr” means cyclopropyl; “Bu” means butyl; “i-Bu” means iso-butyl; “t-Bu” means tert-butyl; “c-Bu” means cyclobutyl; “Hx” means hexyl; “c-C₅H₉” means cyclopentyl; “c-Hx” means cyclohexyl; “B” means boron; “Br” means bromine; “C” means carbon; “Cl” means chlorine; “F” means fluorine; “H” means hydrogen; “I” means iodine; “N” means nitrogen; “O” means oxygen; “P” means phosphorus; “S” means sulfur; “Si” means silicon; and “TBS” means dimethyl-tert-butyl-silyl.

Preparation of Substituted Pyridines

A number of the substituted pyridine compounds and intermediates having pharmacological activity were previously known as herbicides. Accordingly, the specific and/or general procedures for preparing such known compounds can be found in U.S. Pat. Nos. 4,609,399, 4,655,816; 4,692,184; 4,698,093; 4,789,395; 4,885,026; 4,936,905; 4,988,384; 5,037,469; 5,125,961; 5,129,943; 5,156,670; 5,169,432; and 5,260,262; and in Chem. Pharm. Bull., 14, 918 (1966); Biokhimya, 33, 350 (1968); J. Agric Chem., 39, 2072 (1991); Ann., 246, 32 (1888); Res. Discl., 295, 867 (1988); and J. Heterocyclic Chem., 26, 1771 (1989). These references are incorporated herein by reference.

The “Procedure Reference” column of Tables 1-2 provides exemplary references disclosing the specific procedures for the preparation of many of the substituted pyridines identified in those Tables. These references are incorporated herein by reference. One skilled in the art can prepare these compounds based on the disclosure of the references. A reference to “See Example ______” indicates that the procedure, while not specifically for the preparation of the compound listed in the Table, is sufficiently analogous that one skilled in the art can prepare the compound by making the necessary modifications to the referenced procedure without undue experimentation. Additional information for the preparation of a number of these compounds also is set forth below. A written description of the procedures for preparing the remaining substituted pyridines for which no corresponding reference appears in the Tables is set forth below.

The 2,6-dimethyl- and 2,6-bis(methoxymethyl)-3,5-pyridinedicarboxylates (such as Compound 92 and Compound 106) can be prepared by the procedure described in Ann., 246, 32 (1888) and Ann., 241, 1 (1882).

The 5-mercapto analogs II (see, e.g., Example 2 below) can be prepared from the 5-bromo derivative I (which itself can be prepared as shown in U.S. Pat. No. 4,789,395) by reaction with lithium sulfide. The 5-mercapto analogs II can be converted to the disulfide III by oxidation or by reaction with a mixture of 2-fluoroethanol, methanesulfonyl chloride and triethylamine or by reaction with bromine in acetic acid. The 5-mercapto analogs can be reacted with alkyl halides and acyl halides to give the derivatives IV and V cited in this invention. Alternatively pyridyl methylchloride VI can be reacted with a thiol to give the sulfide VII (see, e.g., Example 22 below)

EXAMPLE 1 Preparation of Methyl 2-(Difluoromethyl)-5-mercapto-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 7)

To a stirred solution of 10.11 g (0.026 mol) of methyl 5-bromo-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example 122 of U.S. Pat. No. 5,019,153) in 75 mL dry DMF was added 1.42 g (0.031 mol) of lithium sulfide in one portion and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with 150 mL of 10% HCl solution and extracted with ether (3×100 mL). The combined extracts were washed with water, dried (MgSO₄) and evaporated. The residue was purified by kugelrohr distillation (oven temperature 100-110° C., 1.5 torr) to give 7.35 g (83%) of product as a yellow-green oil:

Anal. Calcd. for C₁₃H₁₄F₅NO₂S: C, 45.48; H, 4.11; N, 4.08 Found: C, 45.58; H, 4.14; N, 4.08.

EXAMPLE 2 Preparation of Dimethyl 5,5′-Dithiobis[2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate] (Compound 181)

To a solution of 1.14 g (0.018 mol) of 2-fluoroethanol and 0.95 g (0.0094 mol) of triethylamine in 20 mL dry THF at −78° C. was added 1.07 g (0.0094 mol) of methanesulfonyl chloride in 10 mL of dry THF. After stirring the mixture for 30 min, 2.5 g (0.0073 mol) of product of example 1 and 0.95 g (0.0094 mol) of triethylamine were added. The mixture was slowly warmed to room temperature and stirred for an additional 2 h. The reaction mixture was evaporated, the residue was diluted with 100 mL of water and extracted with 125 mL of ether. The organic layer was washed with water, dried (MgSO₄) and evaporated. The residue was purified by preparative HPLC (8% ethyl acetate-hexane) to give 1.82 g (73%) of product as a yellow oil:

Anal. Calcd. for C₂₆H₂₆F₁₀N₂O₄S₂: C, 45.61; H, 3.83; N, 4.09 Found: C, 45.80; H, 3.87; N, 4.02

The same compound can be obtained by reacting compound 7 (see Table 1) with one half equivalent of bromine in acetic acid.

EXAMPLE 3 Preparation of Methyl 5-(4-t-Butylphenylthiomethyl)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 3)

Reaction of methyl 5-chloromethyl-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example 3 of U.S. Pat. No. 5,169,432) with 4-t-butylbenzenethiol according to the procedure of example 29 of U.S. Pat. No. 5,169,432 yielded the product as an oil.

Anal. Calcd. for C₁₈H₂₀F₅NO₃: C, 54.96; H, 5.13; N, 3.56. Found: C, 55.05; H, 5.13; N, 3.51.

EXAMPLE 4 Preparation of Ethyl 2,6-Bis(trifluoromethyl)-4-[4-(isopropylphenyl)thio]-5-methyl-3-pyridinecarboxylate (Compound 11)

Reaction of ethyl 2,6-bis(trifluoromethyl)-4-chloro-5-methyl-3-pyridinecarboxylate (example 65 of U.S. Pat. No. 4,655,816) with 4-isopropylbenzenethiol according to the procedure in example 23 of U.S. Pat. No. 4,655,816) yielded the desired product.

EXAMPLE 5 Preparation of Ethyl 2,6-Bis(trifluoromethyl)-4-(isopropoxy)-5-methyl-3-pyridinecarboxylate (Compound 53)

Example 37 of U.S. Pat. No. 4,655,816 discloses a procedure for the preparation of this compound.

EXAMPLE 6 Preparation of Methyl 2,6-bis(Trifluoromethyl)-4-(benzyloxy)-3-pyridinecarboxylate (Compound 37)

Example 9 of U.S. Pat. No. 4,655,816 discloses a procedure for the preparation of this compound.

EXAMPLE 7 Preparation of Methyl 2,6-Bis(trifluoromethyl)-5-(4,5-dihydro-2-thiazoly)-4-(2-methylpropyl)-3-pyridinecarboxylate (Compound 12)

Example 21 of U.S. Pat. No. 4,988,384 discloses a procedure for the preparation of this compound.

EXAMPLE 8 Preparation of Diethyl 2,6-Bis(trifluoromethyl)-4-(2-methylpropyl)-3,5-pyridinedicarboxylate (Compound 36)

Example 7 of U.S. Pat. No. 4,692,184 discloses a procedure for the preparation of this compound.

EXAMPLE 9 Preparation of Di-t-Butyl 2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (Compound 9)

Reaction of the product of step 6 of U.S. Pat. No. 4,988,384 with excess t-butanol according to the procedure of example 56 of U.S. Pat. No. 4,692,184 yielded the product, mp 48-50° C.

EXAMPLE 10 Preparation of Methyl 2-(difluoromethyl)-5-(1-hydroxyl-furylmethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 13)

Reaction of methyl 2-(difluoromethyl)-5-formyl-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (compound B1 of U.S. Pat. No. 5,169,432) with 2-furylithium according to the procedure in Example H of U.S. Pat. No. 5,260,262 yielded the product as an orange oil, n_(D) ²⁵ 1.4863.

EXAMPLE 11 Preparation of Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-[(methoxycarbonyl)thio]-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 6)

To a stirred solution of 3.05 g (0.0089 mol) of product of example 1 and 0.094 g (0.01 mol) of methyl chloroformate in 25 mL dry THF was added 1.16 g (0.012 mol) of triethylamine dropwise at room temperature. After stirring for 30 min, the solvent was evaporated under reduced pressure. The residue was diluted with 100 mL of water and extracted with ether (3×50 mL). The combined organic layers were washed with water, dried (MgSO₄) and evaporated. Purification of the residue by preparative HPLC (5% ethyl acetate-hexane) gave 2.75 g (77%) of product as a yellow oil: n_(D) ²⁵ 1.5830.

Anal. Calcd. for C₁₅H₁₆F₅NO₄S: C, 44.89; H, 4.02; N, 3.49 Found: C, 44.97; H, 4.04; N, 3.47

EXAMPLE 12 Preparation of Methyl 2-(Difluoromethyl)-5-[(i-propylthio)carbonyl]-4-(cyclobutyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 14)

Methyl 5-chlorocarbonyl-4-cyclobutyl-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate prepared similarly to the procedure in step 7 of U.S. Pat. No. 4,988,384 was reacted with 2-propanthiol according to the procedure in example 141 of U.S. Pat. No. 4,692,184 to give the product as an oil, n_(D) ²⁵ 1.4946.

Anal. Calcd. for C₁₇H₁₈F₅NO₃S: C, 49.63; H, 4.41; N, 3.40; S, 7.79.

Found: C, 49.19; H, 4.59; N, 3.19; S, 7.40

EXAMPLE 13 Preparation of Methyl 2,6-Bis(trifluoromethyl)-4-(diphenylaminocarbonyloxy)-3-pyridinecarboxylate (Compound 25)

To a solution of 2 g (0.0069 mol) of methyl 2,6-bis(trifluoromethyl)-4-hydroxy-3-pyridinecarboxylate (example 4 of U.S. Pat. No. 4,655,816) in 20 mL of acetonitrile was added 0.7 g of triethylamine. A solution of 1.6 g (0.0069 mol) of diphenylcarbamyl chloride in 20 mL of acetonitrile was added to the above mixture and the resulting mixture was stirred at room temperature over the weekend. The precipitate formed was filtered off and the filtrate was concentrated in vacuo. The residue was slurried with ether. The insoluble material was filtered. The ether filtrate was concentrated and the residue was recrystallized from cyclohexane to give a white solid, mp 114-116° C.

Anal. Calcd. for C₂₂H₁₄F₆N₂O₄: C, 54.55; H, 2.91; N, 5.78. Found: C, 54.69; H, 3.05; N, 5.69.

EXAMPLE 14 Preparation of 3-Methyl 5-Ethyl 2-(Difluoromethyl)-4-mercapto-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (Compound 2)

To a 5° C. solution of 6 g (0.017 mol) of 3-ethyl 5-methyl 6-(difluoromethyl)-4-chloro-2-(trifluoromethyl)-3,5-pyridinedicarboxylate (example 103 of U.S. Pat. No. 4,698,093) in 50 mL of dry THF was added 1.6 g (0.022 mol) of KSH. The resulting mixture was stirred at 0° C. for 15 min then at room temperature for 16 h. The mixture was poured into 5% NaOH and extracted with ether. The aqueous layer was made acidic with concentrated HCl and the product was extracted into ethyl acetate. The ethyl acetate layer was dried (MgSO₄) and solvent removed in vacuo affording 4.64 g of a light yellow oil. Purification by HPLC (10% MeOH/5% ethyl acetate/85% cyclohexane) gave 3.25 g of a yellow oil, n_(D) ²⁵ 1.4775.

Anal. Calcd. for C₁₂H₁₀F₅NO₄S: C, 40.12; H, 2.81; N, 3.90; S, 8.92.

Found: C, 40.20; H, 2.79; N, 3.86; S, 8.90

EXAMPLE 15 Preparation of Diethyl 2-(Difluoromethyl)-4-(t-butylthio)-6-(trifluoromethyl)-3,5-pyridine-dicarboxylate (Compound 39)

Example 108 of U.S. Pat. No. 4,698,093 discloses a procedure for the preparation of this compound.

EXAMPLE 16 Preparation of Diethyl 2-(Difluoromethyl)-4-(cyclopentylthio)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (Compound 22)

Example 109 of U.S. Pat. No. 4,698,093 discloses a procedure for the preparation of this compound.

EXAMPLE 17 Preparation of Methyl 5-Chloromethyl-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 83)

Example 3 of U.S. Pat. No. 5,169,432 discloses a procedure for the preparation of this compound.

EXAMPLE 18 Preparation of Methyl 2-(Difluoromethyl)-5-(1,3-dioxan-2-yl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 59)

Example 109 of U.S. Pat. No. 4,988,384 discloses a procedure for the preparation of this compound.

EXAMPLE 19 Preparation of Methyl 2-(Difluoromethyl)-5-(methylthiomethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 60)

Example 47 of U.S. Pat. No. 5,169,432 discloses a procedure for the preparation of this compound.

EXAMPLE 20 Preparation of Dimethyl 2-(Difluoromethyl)-4-{[(2-methylthio)pyrimidin-4-yl]methyl}-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (Compound 67)

To a solution of 7.1 g (0.021 mol) of dimethyl 2-(difluoromethyl)-4-methyl-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (example 218 of U.S. Pat. No. 4,692,184) in 90 mL of anhydrous THF cooled to −30° C. under nitrogen was added 25 mL (0.025 mol) of 1.0 M lithium bis(trimethylsilyl)amide in THF controlling the temperature range at −20° C. to −30° C. After 15 min at −30° C. a solution of 5.0 g (0.031 mol) of 4-chloro-2-methylthio-pyrimidine in 20 mL of THF was added. The mixture is allowed to warm to −10° C., where it was held for 1.5 h. The reaction mixture was added to diluted HCl and worked up with methylene chloride. The product was purified by HPLC (12% ethyl acetate in hexane), and by recrystallization from hexane to give amber-yellow solid, mp 89-91° C.

Anal. Calcd. for C₁₇H₁₄F₅N₃O₄S: C, 45.24; H, 3.13; N, 9.31. Found: C, 45.27; H, 3.15; N, 9.26.

EXAMPLE 21 Preparation of Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-5-[(trimethylsilyl)ethynyl]-3-pyridinedicarboxylate (Compound 19)

A mixture of 6 g (0.015 mol) of methyl 5-bromo-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example 122 of U.S. Pat. No. 5,019,153), 0.1 g of palladium (II) acetate, 0.2 g of triphenylphosphine, 30 ml of triethylamine and 5 g of (trimethylsilyl)acetylene was held at reflux under nitrogen for 4 hours and cooled to room temperature. The reaction mixture was filtered through a small plug of celite and the filtrate was concentrated in vacuo to give a dark oil. The residue was Kugelrohr distilled to give 5 g of light brown oil which was purified by Chromatotron (9:1 cyclohexane/methylene chloride). A total of 3 g (48% yield) of a yellow oil (n_(D) ²⁵ 1.4681).

The 5-arylthiomethyl- and 5-heteroarylthiomethylpyridines shown in Table 6 can be prepared by reaction of an arylthiol or a heteroarylthiol with substituted 5-pyridylmethyl halide in the presence of base similar to the procedure in Example 3. The following procedures describe a typical synthesis of these compounds.

General Procedure for the Preparations of Sulfides X from IX.

To a solution of 1 mmol of triethylamine in 50 mL of THF was added 1 mmol of an arylthiol or a heteroarylthiol and 1 mmol of IX. The reaction mixture was stirred overnight and filtered to remove triethylamine hydrochloride. The filtrate was diluted with 50 mL of ether and washed with water. The ether layer was dried (MgSO₄) and concentrated in rotovap to give the product.

The 5-aryl- and heteroaryl-methylthiopyridines shown in Table 7 can be prepared by reaction of compound 7 with the appropriate arylmethyl chloride or heteroarylmethyl chloride.

General Procedure for the Preparations of Sulfides XI

To a solution of 1 mmol of arylmethyl chloride and 1 mmol of methyl 2-(difluoromethyl)-4-isobutyl-5-mercapto-6-(trifluoromethyl)-3-pyridinecarboxylate (compound 7) in 50 mL of DMF was added 1 mmol of triethylamine. The reaction mixture was stirred until TLC showed that the reaction was mostly complete. The reaction mixture was diluted with ethyl acetate and washed successively with 1 N KHSO₄, water, 10% sodium hydroxide (to remove unreacted methyl 2-(difluoromethyl)-4-isobutyl-5-mercapto-6-(trifluoromethyl)-3-pyridinecarboxylate) and brine, dried (Na₂SO₄) and concentrated in rotovap. If necessary, the residue was purified by HPLC or chromatotron.

EXAMPLE 22 Preparation of Methyl 5-{[3-(Carbomethoxy)-2-(difluoromethyl)-4-isobutyl-6-(trifluoromethyl)-5-pyridyl]thiomethyl}-2-(difluoromethyl)-4-isobutyl-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 182)

To a solution of 550 mg (1.53 mmol) of 5-chloromethyl-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example 3 of U.S. Pat. No. 5,169,432) and 524 mg (1.53 mmol) of methyl 2-(difluoromethyl)-4-isobutyl-5-mercapto-6-(trifluoromethyl)-3-pyridinecarboxylate (compound 7) in 50 mL of DMF was added 154 mg (1.53 mmol) of triethylamine. The reaction mixture was stirred for 40 h, diluted with ethyl acetate (400 mL) and washed successively with 1 N KHSO₄ (200 mL) and brine (100 mL), dried (Na₂SO₄), and concentrated in a rotovap. The residue was purified by flash chromatography (10% EtOAc-hexane) to give 550 mg of material. TLC showed that this material contained product, compound 7 and disulfide of compound 181. A 110 mg of this material was further purified by HPLC (0-40% EtOAc-Hexane) to give pure product.

Reaction of compound 7 with the appropriate alkyl halide or acid chloride in THF in the presence of one equivalent of triethylamine with the procedure similar to Example 22 and Example 6 gave compounds 5, 33, 44, 145, 146, 147, and 183. Compound 148 was isolated as a byproduct from Example 2. The following example describes a typical procedure for the synthesis of these compounds.

EXAMPLE 23 Preparation of Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(palmitoylthio)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 5)

To a solution of 0.5 g of palmitoylchloride in 50 ml of THF was added 0.62 g of compound 7 followed by 0.37 g of triethylamine. The reaction mixture was stirred for 1 h, poured into water and extracted with ether. The ether extract was dried over MgSO₄ and concentrated in vacuo to give the product.

The compounds in Table 3 and Table 4 are prepared from reaction of methyl 5-chlorocarbonyl-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (product of step 7 in U.S. Pat. No. 4,988,384) with appropriate the phenols and thiophenols. The following example describes a typical procedure for the synthesis of these compounds.

EXAMPLE 24 Preparation of Methyl 2-(Difluoromethyl)-5-{[(2,4-dimethyl-phenyl)thio]carbonyl}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 158)

To a solution of 1 g of 2,4-dimethylbenzenethiol and 3.29 g of methyl 5-chlorocarbonyl-2-(difluoromethyl)-4-2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate in 50 ml of THF was added 0.81 g of potassium t-butoxide. The reaction mixture was stirred for 1 h and poured into ice-water. The organic was extracted into methylene chloride. The methylene chloride extract was dried over MgSO₄ and concentrated in vacuo. The residue was recrystallized from ether-hexane to give 2.73 g of the product.

The unsymmetric aryl pyridyl disulfides can be prepared by oxidation of a mixture of the appropriate pyridinethiol and arylthiol with bromine in acetic acid followed by separation of the unsymmetric aryl pyridyl disulfide from the symmetric diaryl disulfide and dipyridyl disulfide by chromatography. The following example describes a typical procedure for the synthesis of these compounds.

EXAMPLE 25 Preparation of Methyl 5-(4-t-Butylphenyldithio)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 180)

To a mixture of 100 mg of compound 7 and 48.6 mg of 4-t-butylbenzenethiol in 5 ml of acetic acid was added 23 mg of bromine. The reaction mixture was stirred for 1 h, poured into water and extracted with ether. The ether extract was washed with saturated sodium bicarbonate, dried over MgSO₄ and concentrated in vacuo. The residue was purified by preparative TLC (9:1 Hexane: EtOAc) on silica gel to give the desired product.

EXAMPLE 26 Preparation of Dimethyl 2,6-Bis(trifluoromethyl)-4-(trimethylsilyl)-3,5-pyridinedicarboxylate (Compound 31)

To 10 ml of dry THF at −78° C. was added 8.4 ml (0.012 mol) of 1.55 M n-butyllithium in hexane followed by 1.21 g (1.7 ml, 0.012 mol) of diisopropylamine. After stirring at −78° C. for 30 min, a solution of 3.59 g (0.01 mol) of diethyl 2,6-bis(trifluoromethyl)-3,5-pyridine-dicarboxylate (prepared by the procedure similar to example 1 of U.S. Pat. No. 4,692,184) in 10 ml of dry THF was added. The reaction turned dark red and after stirring at −78° C. for 10 min, 4.4 g (0.05 mol) of chlorotrimethylsilane was added. The reaction was warmed to room temperature, stirred for 30 min and then was poured into 0° C. water, extracted with ether, dried (MgSO₄) and concentrated in vacuo. The residue was purified by HPLC (1:20 EtOAc:hexane) affording 2.09 g of the product as a light yellow oil which crystallized upon standing: mp 29-31° C.

EXAMPLE 27 Preparation of Diethyl 5,5′-(Carbonyldiimino)bis [6-(difluoromethyl)-4-ethyl-2-(trifluoromethyl)-3-pyridinecarboxylate (Compound 48)

A mixture of 2-(difluoromethyl)-5-ethoxycarbonyl-4-ethyl-(6-trifluoromethyl)-3-pyridinecarboxylic acid (example 28 of U.S. Pat. No. 4,692,184)and 40 ml of thionyl chloride was held at reflux for 1 h and concentrated in vacuo. The residue was dissolved in 50 ml of toluene and treated with 20 g of sodium azide and 0.1 g of 18-crown-6 (Aldrich). The reaction mixture was held at reflux for 24 h and filtered. The filtrate was treated with 50 ml of concentrated HCl and stirred for 18 h. The reaction mixture was treated with 50 ml of water and the toluene layer was separated and concentrated in vacuo. The residue was treated with 40 ml of trifluoroacetic acid and 10 ml of water then was held at reflux for 30 min and concentrated in vacuo. The residue was stirred with water and extracted with ether. The ether layer was washed with saturated sodium bicarbonate, dried (MgSO₄) and concentrated in vacuo to give 7.9 g of syrup. This syrup was stirred with ether and filtered to give 0.58 g of product, mp 219-221° C.

EXAMPLE 28 Preparation of Dimethyl 5,5′-Carbonylbis[4-(1-methylethoxy)-2-(trifluoromethyl)-3-pyridinecarboxylate (Compound 54)

Step 1: Methyl 4-Hydroxy-2-(trifluoromethyl)-3-pyridinecarboxylate.

A mixture of 105 g (0.5 mol) of methyl 2-acetyl-3-amino-4,4,4-trifluoro-2-butenoate (example 2 of U.S. Pat. No. 4,655,816), acetic anhydride (152 g), and trimethyl orthoformate (106 g) was held at reflux for 16 h then distilled to remove low boiling material (bp 65-90° C.). The remaining material was concentrated in vacuo and the residue was kugelrohr distilled at 2 torr (80-120° C.) to give 114 g of distillate. This distillate (44 g) was added dropwise to a mixture of 14.5 g of 60% sodium hydride oil dispersion in 100 ml of 1,2-dimethoxyethane (DME). The reaction mixture was maintained at 25-30° C. with an ice-water bath. The reaction mixture was stirred at room temperature for 18 h and poured into 300 ml of ice-water. The aqueous layer was extracted with ether and filtered. The aqueous layer was acidified with concentrated HCl. The oil precipitate was extracted into ether. The ether extract was extracted with 10% potassium carbonate. The potassium carbonate layer was acidified with concentrated HCl. The precipitate was filtered and air dried to give 20.4 g of the product, mp 78-82° C.

Step 2: Methyl 4-(1-Methylethoxy)-2-(trifluoromethyl)-3-pyridinecarboxylate (Compound 127).

A mixture of 7.0 g of product of step 1, 4.74 g of potassium carbonate, 14 g of 2-iodopropane and 50 ml of acetone was held at reflux for 18 h and concentrated in vacuo. The residue was treated with water and extracted with ether. The ether extract was dried (MgSO₄) and concentrated in vacuo. The residue was crystallized from hexane at low temperature to give 6.2 g of solid, mp 57.5-58.5° C.

Compound 121 in Table 1 was similarly prepared except using ethyl 2-acetyl-3-amino-4,4,4-trifluoro-butenoate (example 1 of U.S. Pat. No. 4,655,816) as the starting material in step 1.

Step 3: Dimethyl 5,5′-Carbonylbis[4-(1-methylethoxy)-2-(trifluoromethyl)-3-pyridinecarboxylate, Compound 54.

To a cold (−78° C.) solution of 20 ml dry DME was added 11.5 ml of 1.6 M butyllithium in hexane followed by 2.5 ml of diisopropylamine. The reaction mixture was stirred for 10 min. To the above solution was added a solution of 4.2 g of product of step 2 in 15 ml of dry DME. The reaction mixture turned orange. After 5 min stirring, 3.3 ml of ethyl chloroformate was added to the reaction mixture. After 10 min stirring, the reaction mixture was poured into water and extracted with ether. The ether extract was dried (MgSO₄) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20% EtOAc in hexane) to give 3.45 g of oil which was crystallized from hexane to give 2.2 g of solid, mp 74-75° C.

EXAMPLE 29 Preparation of Methyl 2-(Difluoromethyl)-4-cyclobutyl-5-(1-pyrrolyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 70)

A solution of 1.62 g (5 mmol) of methyl 5-amino-2-(difluoromethyl)-4-cyclobutyl-6-(trifluoromethyl)-3-pyridinecarboxylate (example A-2 of U.S. Pat. No. 5,114,465) and 0.8 g (6 mmol) of 2,5-dimethoxytetrahydrofuran in 10 ml of acetic acid as heated at 70° C. for 2.5 h. The reaction mixture was then diluted with 100 ml of water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate (3×100ml), dried (MgSO₄) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (10% EtOAc in hexane) to give the product, mp 70-71° C.

EXAMPLE 30 Preparation of Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-(aminothionocarbonyl)-6-(trifluoromethyl) -3-pyridinecarboxylate (Compound 77)

To 16.5 g of methyl 6-(difluoromethyl)-4-(2-methylpropyl)-5-(methoxycarbonyl)-2-(trifluoromethyl)-a-oxo-3-pyridineacetate (prepared by example E of U.S. Pat. No. 5,298,479) in 60 ml of methylene chloride was added 25 ml of concentrated ammonium hydroxide. The reaction mixture was stirred for 2 h and the aqueous layer was saturated with NaCl and the organic was extracted into methylene chloride. The methylene chloride layer was dried (MgSO₄) and concentrated in vacuo. The residue was recrystallized from 20% EtOAc-benzene to give 12.5 g of 6-(difluoromethyl) -4-(2-methylpropyl)-5-(methoxy-carbonyl)-2-(trifluoromethyl)-a-oxo-3-pyridineacetamide. A mixture of 2.4 g of this material, 2.0 g of phosphorus pentasulfide, 2 g of Celite and 16 ml of toluene was held at reflux for 2h. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20% EtOAc in hexane) to give an oil which crystallized from 3% EtOAc in hexane as a solid.

EXAMPLE 31 Preparation of Methyl 2-(Difluoromethyl)-4-(2-methylpropyl)-5-[(tetrahydro-2-furyl)thio]-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 150)

A mixture of 7.07 g (0.021 mol) of compound 7, 2.92 g (0.042 mol) of dihydrofuran, and catalytic toluenesulfonic acid (9 mg) in 80 ml of ether was stirred overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by HPLC (20% EtOAc in hexane) to give 5.82 g (68%) of the desired product as a yellow oil, n²⁵D 1.5803.

EXAMPLE 32 Preparation of Dimethyl 2,6-Bis(methoxymethyl)-4-propyl-3,5-pyridinedicarboxylate (Compound 92)

A solution of 4.93 g (0.068 mol) of n-butyraldehyde, 20 g (0.137 mol) of methyl 4-methoxyacetoacetate, 15 ml of ethanol, and 6.8 ml of concentrated ammonium hydroxide was held at reflux for 5 h and poured into 200 ml of ice water. The oil which precipitated out was extracted into ether. The ether layer was washed with water, dried (MgSO₄), and concentrated in vacuo. The residue was purified by HPLC (10% EtOAc in hexane) to give 7.91 g of yellow solid. Recrystallization from hexane gave 6.44 g of dimethyl 2,6-bis(methoxymethyl)-1,4-dihydro-4-propyl-3,5-pyridinedicarboxylate as yellow solid. A solution of this solid (4.35 g, 0.0133 mol) in 75 ml of 70% acetic acid was heated to 70° C. Chromium trioxide (3.99 g, 0.0399 mol) was added slowly. The reaction mixture was stirred at 65-70° C. for 1 h and poured into ice water and extracted with ether. The combined ether layers were stirred with 500 ml of saturated sodium bicarbonate. The ether layer was dried (MgSO₄) and concentrated in vacuo. The residue was kugelrohr distilled at 140° C. at 1 torr to give an oil, n²⁵D 1.4924.

EXAMPLE 33 Preparation of Methyl 5-[(Diethoxyphosphinyl)carbonyl]-2-(difluoromethyl)-4-(1-methylethylamino)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 85)

A mixture of 46.27 g (0.1 mol) of 3-methyl 5-benzyl 2-(difluoromethyl)-4-(1-methylethylamino)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (example 181 of U.S. Pat. No. 4,698,093) in 1.2 L of a 1:5 mixture of THF in methanol was hydrogenated using catalytic 5% Pd/C under 50 lb of hydrogen pressure for 48 h. The reaction mixture was filtered through Celite and concentrated in vacuo to give 36 g of 3-methyl 5-hydrogen 2-(difluoromethyl)-4-(1-methylethylamino)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate. To a mixture of 34.7 g of this monoacid in 400 ml of carbon tetrachloride was added 23 g (0.11 mol) of phosphorus pentachloride. The reaction mixture was stirred at room temperature until HCl evolution stopped. The reaction mixture was held at reflux for 20 min and concentrated in vacuo affording 38.04 g of monoacid chloride as a yellow oil. A portion (3.75 g 0.01 mol) of this oil and 1.7 g (0.01 mol) of triethyl phosphite was heated to 160° C. and then cooled. The resulting oil was purified by HPLC (25% EtOAc in hexane) affording 2.09 g of (44%) of product as a thick yellow oil.

EXAMPLE 34 Preparation of Methyl 2-(Difluoromethyl)-5-{[methoxy (methylthio)methylene]amino)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 27)

To a solution of 2.5 g (6.8 mmol) of methyl 2-(difluoromethyl)-5-isothiocyanato-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (U.S. Pat. No. 5,129,943 example 41 step A) in 25 ml of anhydrous THF at room temperature was added 1.6 g (7.5 mmol) of 25% sodium methoxide in methanol. The reaction mixture was stirred for 30 min and was treated with 1.93 g (14 mmol) of methyl iodide. The reaction mixture was stirred for 3 h and concentrated in vacuo. The residue was partitioned with ether (75 ml) and 10% HCl (50 ml). The organic layer was washed with water (3×30 ml), dried (MgSO₄), and concentrated in vacuo. The crude product was purified by chromatotron (20% EtOAc in hexane) to afford 2.32 g (82%) of a colorless oil, n²⁵D 1.5982.

EXAMPLE 35 Preparation of Methyl 5-{[Bis(methylthio)methylene]amino}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 42)

This was prepared similar to example 33 except sodium methanethiolate was used instead of sodium methoxide. The product was isolated as a colorless oil, n²⁵D 1.5850.

EXAMPLE 36 Preparation of Methyl 2-(Difluoromethyl)-4-(2-methyl-propyl)-5-((oxiranylmethoxy)methylene]amino}-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 30)

A slurry of 10.0 g (0.028 mol)of methyl 2-(difluoromethyl)-5-formylamino-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (U.S. Pat. No. 5,037,469 example G1) and 6.03 g (0.029 mol) of phosphorus pentachloride in 75 ml of CCl₄ was stirred overnight at room temperature. The solvent was evaporated to give crude imidoyl chloride.

To a stirred solution of 6.02 g (0.0163 mol) of the crude imidoyl chloride in 75 ml of anhydrous THF at room temperature was added 6.43 g (0.087 mol) of glycidol in one portion followed by 2.53 g (0.021 mol) of 4-dimethylaminopyridine. The reaction mixture was held at reflux for 3 h and concentrated in vacuo. The residue was partitioned with ether (100 ml) and water (50 ml). The organic layer was washed with 10% HCl (3×30 ml) and saturated sodium bicarbonate (3×30 ml), dried (MgSO₄), and concentrated in vacuo. The crude product was purified by chromatotron (20W EtOAc in hexane) to afford 2.58 f (38%) of a solid, mp 41-43° C.

EXAMPLE 37 Preparation of Methyl 2-(Difluoromethyl)-5-(iodomethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 32)

Reaction of methyl 2-(difluoromethyl)-5-(chloromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (U.S. Pat. No. 5,169,432 example 3) with sodium iodide in refluxing acetone according to the procedure known to those in the art yielded the product.

Compound 13 was prepared by the procedure in example H of U.S. Pat. No. 5,260,262. Compounds 89, 105, 131, and 133 were similarly prepared.

Compounds 34 and 40 were prepared from the 5-[(heteroaryl)hydroxymethyl] compounds which were prepared by the procedure H of U.S. Pat. No. 5,260,262. The following example described the preparations of these compounds.

EXAMPLE 38 Preparation of Methyl 2-(Difluoromethyl)-5-[(methoxy) isothiazol-5-ylmethyl]-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 34)

Methyl 2-(difluoromethyl)-5-[(isothiazol-5-yl) hydroxymethyl]-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (prepared by the procedure similar to example H of U.S. Pat. No. 5,260,262) was alkylated with methyl iodide by the procedure in example 61 of U.S. Pat. No. 5,169,432.

EXAMPLE 39

Methyl 5-(Benzoyloxymethyl)-2-(difluoromethyl)4-(cyclopropylmethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 41)

Reaction of methyl 2-(difluoromethyl)-5-(hydroxymethyl)-4-(cyclopropylmethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (U.S. Pat. No. 5,169,432 example A compound A4) with. Benzoyl chloride and triethylamine according to the procedure in example 99 of U.S. Pat. No. 5,169,432 gave the product.

EXAMPLE 40 Preparation of Methyl 2-(difluoromethyl)-5-{[isopropylimino(methylthio)methyl]}-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 58)

Reaction of methyl 5-chlorocarbonyl-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (step 7 of U.S. Pat. No. 4,988,384) with isopropylamine yielded the corresponding isopropylamide. A mixture of this amide (3.75 g), 1.97 g of PCl₅ and 150 ml of carbon tetrachloride was held at reflux overnight and concentrated in vacuo. The residue was dissolved in 60 ml of THF and cooled to 5° C. and treated with 0.27 g of sodium methanethiolate. The reaction mixture was stirred at room temperature overnight, poured into water and extracted into ether. The organic was dried (MgSO₄), filtered, and concentrated in vacuo. The residue was purified by chromatotron (20% EtOAc in hexane) to give 1.0 g of pale yellow oil.

Compound 68 in Table 1 was similarly prepared except using methylamine instead of isopropylamine as a reagent.

EXAMPLE 41 Preparation of 3-Ethyl 5-Isopropyl 4-hydroxy-2-(trifluoromethyl)-3,5-pyridinedicarboxylate (Compound 101)

Ethyl 4-i-propoxy-2-(trifluoromethyl)-3-pyridinecarboxylate (prepared similar to step 2 of example 28) was reacted with 2 equivalents of lithium diisopropylamide as in step 3 of example 28 and quenched with dry ice instead of ethyl chloroformate. The reaction mixture was stirred at −78° C. for 15 min then warmed to room temperature in 1 h. The reaction mixture was poured into water and extracted with ether. The aqueous layer was acidified with concentrated HCl to give 3-ethyl 5-hydrogen 4-isopropoxy-2-(trifluoromethyl)-3, 5-pyridinedicarboxylate as a solid, mp 97-99° C. A mixture of 10 g of this acid and 25 ml of thionyl chloride was held at reflux for 1 h and concentrated. The residue was held at reflux with 15 ml of isopropanol for 1 h and concentrated. The residue was kugelrohr distilled at 0.15 torr to give product as an oil, n²⁵D 1.4620.

Compound 125 was similarly prepared except using ethanol instead of isopropanol as a reagent.

EXAMPLE 42 Preparation of Methyl 4-(Cyclopropylmethyl)-2-(difluoromethyl)-5-(1-hydroxy-5-methyl-3-pyrrolidinyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 107)

To a solution of 16.5 g (68.3 mmol) of methyl 5-(1-cyano-3-butenyl)-4-(cyclopropylmethyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example 16 of U.S. Pat. No. 5,169,432) in 250 ml of ether cooled in an ice bath was added 91 ml (136 mmol) of diisobutylaluminum hydride (1.5 M in toluene). The reaction mixture was stirred on an ice bath for 30 min and was treated with 200 ml of 2.4 M HCl. The organic layer was washed with brine, dried (MgSO₄), and filtered through silica gel. The filtrate was concentrated in vacuo and the residue was purified by HPLC (17% EtOAc in hexane) to give 8.1 g of methyl 4-(cyclopropylmethyl)-2-(difluoromethyl)-5-(1-formyl-3-butenyl)-6-(trifluoromethyl)-3-pyridinecarboxylate.

To a solution of 5.8 g (14.8 mmol) of the above aldehyde in 100 ml of Ccl₄ was added 1.1 g (15.8 mmol) of hydroxylamine hydrochloride. To the mixture was added 10 g of pyridine and the mixture was heated to reflux for 1.5 h. The reaction mixture was partitioned between ether and 2.4 M HCl. The organic layer was washed with brine, dried (MgSO₄), and filtered through silica gel, and the filtrate was concentrated in vacuo. The residue was purified by HPLC (15% EtOAc in hexane) to yield 1.6 g of the oxime as white crystals, mp 98.5-101° C.

To a solution of 3.0 g (7.4 mmol) of the above oxime and 0.5 g (7.9 mmol) of sodium cyanoborohydride in 30 ml of methanol was added 3 mg of methyl orange. To the resulting solution was added dropwise a solution of conc. HCl and methanol (1:1) at a rate to maintain a reddish color (pH ˜3.4). After the red color remained (1 h) the reaction mixture was partitioned between ether and 10% NaOH. The organic was washed with brine, dried (MgSO₄), and filtered through silica gel, and the filtrate was concentrated in vacuo. The residue was purified by HPLC (35% EtOAc in hexane) to give two fractions. The first fraction amounted to 0.8 g (27% yield) of crystals which was the desired product, mp 141.5-143.5° C. The second fraction amounted to 1.5 g (50% yield) of a colorless oil identified as the other diastereomer.

EXAMPLE 43 Preparation of Ethyl 4-Hydroxy-5-phenoxy-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 109)

Ethyl 2-(1-amino-2,2,2-trifluoroethylidien)-3-oxo-4-phenoxy-butanoate (example B1 of U.S. Pat. No. 4,936,905) was reacted according to the procedure in step 1 of Example 28 to give the product.

EXAMPLE 44 Preparation of Methyl 2-(difluoromethyl)-4-(2-methylpropyl)-5-(2-oxazolyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 110)

This compound was prepared according to the procedure in example 4 of U.S. Pat. No. 4,988,384 except ethanolamine was used instead of glycine methyl ester hydrochloride.

EXAMPLE 45 Preparation of Methyl 5-(Chloroethylsulfinyl)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 111)

Oxidation of compound 44 with one equivalent of MCPBA according to the procedure in example 21 of U.S. Pat. No. 4,789,395 gave the product.

EXAMPLE 46 Preparation of Methyl 4-(Cyclopropylmethyl)-2-(difluoromethyl)-5-[imino(methylthio)methyl]-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 112)

Step 1: Methyl 5-(aminothioxomethy)-4-(Cyclopropylmethyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate.

Methyl 5-chlorocarbonyl-4-(cyclopropylmethyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example B3 of U.S. Pat. No. 5,156,670) was converted to methyl 4-(cyclopropylmethyl)-5-cyano-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate by the procedure similar to example 88 and 92 of U.S. Pat. No. 4,692,184. A solution of 20 g (60 mmol) of this cyano compound and 0.62 g (6 mmol) of diethylamine in 60 ml of DMF was heated to 50° C. Hydrogen sulfide gas was introduced into this solution. When absorption of hydrogen sulfide was complete the reaction mixture was stirred at 50° C. for 1 h and poured into water and extracted with ether. The ether extract was washed with brine, dried (MgSO₄), and concentrated in vacuo. The residue was kugelrohr distilled to give 17.7 g (80% yield) of yellow oil.

Step 2: Methyl 4-(Cyclopropylmethyl)-2-(difluoromethyl)-5-[imino(methylthio)methyl]-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 112)

A solution of 3.7 g (10 mmol) of product of step 1 in 20 ml of methylene chloride was treated with 1.24 ml (11 mmol) of methyl trifluoromethylsulfonate. The reaction mixture as stirred under nitrogen at room temperature overnight and diluted with 80 ml of methylene chloride and washed with a saturated sodium bicarbonate solution. The methylene chloride solution was dried (MgSO₄), and concentrated in vacuo. The residue was purified by chromatography (EtOAc: hexane=1:5) to give 2.30 g (60%) of a yellow oil, n²⁵D 1.5059.

Compound 90 in Table 1 was similarly prepared except using methyl 5-(chlorocarbonyl)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate as the reagent.

EXAMPLE 47 Preparation of Ethyl 5-Ethoxy-4-Hydroxy-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 114)

Ethyl 3-amino-2-(2-ethoxy-1-oxo-ethyl)-4,4,4-trifluoro-2-butenoate (example A2 of U.S. Pat. No. 4,936,905) was reacted according to the procedure in step 1 of example 28 to give the product.

EXAMPLE 48

Methyl {-[2-Chloro-4-(trifluoromethyl)-5-thiazolyl]carbonylamino}-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 117)

Methyl 5-amino-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example A1 of U.S. Pat. No. 5,114,465) was reacted with 2-chloro-4-(trifluoromethyl)-5-thiazolecarbonyl chloride according to the procedure in example 1 of U.S. Pat. No. 5,114,465 afforded the product.

EXAMPLE 49 Preparation of Methyl 5-(aminothioxomethyl)-4-(cyclobutyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 119)

This compound was prepared from methyl 5-(chloro-carbonyl)-4-(cyclobutyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate according to the procedure in step 1 of Example 46.

Compound 103 in Table 2 was made similarly except using methyl 5-chlorocarbonyl-4-(2-methylpropyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (step 7 of U.S. Pat. No. 4,988,384) as the starting material.

EXAMPLE 50 Preparation of 4-(4-Isopropylphenylthio)-5-methyl-6-(trifluoromethyl)-3-pyridinecarboxylic Acid (Compound 126)

Methyl 4-(4-isopropylphenylthio)-5-methyl-6-(trifluoromethyl)-3-pyridinecarboxylate (compound 11) was hydrolyzed with sodium hydroxide to give the product.

EXAMPLE 51

Methyl 5-(aminoethylthiocarbonyl)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 134)

Reaction of methyl 5-(chlorocarbonyl)-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridine carboxylate (step 7 of U.S. Pat. No. 4,988,384) with 2-mercaptoethylamine similar to the procedure in example 140 of U.S. Pat. No. 4,692,184 gave the product.

EXAMPLE 52 Preparation of Methyl 5-(1-Bromo-2-methoxyethenyl)-4-(cyclopropylmethyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 35)

To a solution of 18.0 g (49.3 mmol) of methyl 4-(cyclopropylmethyl)-2-(difluoromethyl)-5-(2-methoxyethenyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example 127 of U.S. Pat. No. 6,169,432) in 250 ml of ether was added 7.9 g (49.4 mmol) of bromine. The reaction mixture was stirred at room temperature for 2 h and to the mixture was added 6.8 g of freshly ground potassium carbonate and 100 ml of methanol. The reaction mixture was stirred for another 45 min and was washed with water and brine. The organic layer was dried (MgSO₄), filtered through celite, and concentrated in vacuo. The residue was kugelrohr distilled and the distillate was purified by chromatography (7% EtOAc in hexane) to give 18.7 g (80% yield) of 1:1 mixture of methyl 5-(1-bromo-2,2-dimethoxy-ethyl)-4-(cyclopropylmethyl)-2-(difluoromethyl)-6-(trifluoromethyl)-3-pyridinecarboxylate and product. HPLC purification (10% EtOAc in hexane) gave 4.1 g of the desired product as a colorless oil which crystallized and was recrystallized from hexane to give crystals, mp 79-79.5° C.

EXAMPLE 52 Preparation of Methyl 2-(Difluoromethyl)-5-[(dimethylaminothionothio)methyl]-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 43)

To a solution of 0.91 g (20 mmol) of dimethylamine in 6 ml of water and 0.92 g of 50% NaOH at 0° C. was added 0.95 g (12.5 mmol) of carbon disulfide. The reaction mixture was stirred for 1 h and to the reaction mixture was added a solution of 3.6 g (10 mmol) of 5-chloromethyl-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example 3 of U.S. Pat. No. 5,169,432) in 10 ml of acetone. The reaction mixture was quenched with water, extracted with methylene chloride, dried (MgSO₄), filtered through celite, and concentrated in vacuo. The residual brown solid was crystallized from ethyl acetate-hexane to give 3.21 g (72% yield) of product, mp 91-92° C.

EXAMPLE 53 Preparation of Methyl 2-(Difluoromethyl)-5-[(dimethylaminothionothio)methyl]-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 79)

This compound was made by the procedure similar to example 52 except gaseous carbonyl sulfide was used to replace carbon disulfide. The product was isolated as white power, mp 80-81° C.

BIOLOGICAL ACTIVITY EXAMPLES EXAMPLE 54

CETP Activity In Vitro

The ability of compounds to inhibit CETP were assessed using an in vitro assay that measured the rate of transfer of radiolabeled cholesteryl ester ([³H]CE) from HDL donor particles to LDL acceptor particles. Details of the assay are provided by Glenn et al. (“Quantification of Cholesteryl Ester Transfer Protein (CETP): A) CETP Activity and B) Immunochemical Assay of CETP Protein,” Meth. Enzymol., Glenn and Melton (Meth. Enzymol., 263, 339-351 (1996), which is incorporated herein by reference). CETP was obtained from the serum-free conditioned medium of CHO cells transfected with a cDNA for CETP (Wang, S. et al. J. Biol Chem. 267, 17487-17490 (1992), which is incorporated herein by reference).

To measure CETP activity, [³H]CE-labeled HDL, LDL, CETP and assay buffer (50 mM tris(hydroxymethyl)amino-methane, pH 7.4; 150 mM sodium chloride; 2 mM ethylenediamine-tetraacetic acid; 1% bovine serum albumin) were incubated in a volume of 200 μl, for 2 hours at 37° C. in 96 well plates. LDL was differentially precipitated by the addition of 50 μl of 1% (w/v) dextran sulfate/0.5 M magnesium chloride, mixed by vortex, and incubated at room temperature for 10 minutes The solution (200μl) was transferred to a filter plate (Millipore). After filtration, the radioactivity present in the precipitated LDL was measured by liquid scintillation counting. Correction for non-specific transfer or precipitation was made by including samples that did not contain CETP. The rate of [³H]CE transfer using this assay was linear with respect to time and CETP concentration, up to 25-30% of [³H]CE transferred.

The potency of test compounds was determined by performing the above described assay in the presence of varying concentrations of the test compounds and determining the concentration required for 50% inhibition of transfer of [³H]CE from HDL to LDL. This value was defined as the IC₅₀. The IC₅₀ values determined by this method for the substituted pyridine compounds of the invention are specified in Tables 1-8.

EXAMPLE 55

Whole Serum CETP Activity Assay (Tritiated Cholesterol Ester)

Blood was obtained from healthy volunteers recruited from the personnel of Monsanto Company, Saint Louis, Mo. Blood was either collected in tubes containing EDTA (EDTA plasma pool) or in tubes without EDTA (spun to form the serum pool). The EDTA human plasma pool or human serum pool, previously stored at −20° C., was thawed at room temperature, and centrifuged for 5 minutes to remove any particulate matter. Tritiated HDL, radiolabeled in the cholesteryl ester moiety ([³H]CE-HDL) as described by Morton and Zilversmit (J. Biol. Chem., 256, 11992-95 (1981) which is incorporated by reference herein), was added to the plasma or serum to a final concentration of (25 μg/ml cholesterol).

Inhibitor compounds were added to the plasma or serum as follows: Equal volumes of the plasma or serum containing the [³H]CE-HDL (396 μl) were pipetted into micro tubes (Titertube®, Bio-Rad Laboratories, Hercules, Calif.). Compounds, usually dissolved as 20-50 mM stock solutions in DMSO, were serially diluted in DMSO (or an alternative solvent in some cases, such as dimethylformamide or ethanol). Four μl of each of the serial dilutions of inhibitor compounds or DMSO alone were then added to each of the plasma or serum tubes. The tubes were immediately mixed. Triplicate aliquots (100 μl) from each plasma or serum tube were then transferred to wells of 96-well round-bottomed polystyrene microtiter plates (Corning, Corning, N.Y.). Plates were sealed with plastic film and incubated at 37° C. for 4 hours.

Test wells contained plasma or serum with dilutions of inhibitor compounds. Control wells contained plasma or serum with DMSO alone. Blank wells contained plasma or serum with DMSO alone that were left in the micro tubes at 4° C. for the 4 hour incubation and were added to the microtiter wells at the end of the incubation period. VLDL and LDL were precipitated by the addition of 10 μl of precipitating reagent (1% (w/v) Dextran Sulfate (Dextralip50)/0.5M magnesium chloride, pH 7.4) to all wells. The wells were mixed on a plate mixer and then incubated at ambient temperature for 10 min. The plates were then centrifuged at 1000×g for 30 mins at 10° C. The supernatants (50 μl) from each well were then transferred to Picoplate™ 96 plate wells (Packard, Meriden, Conn.) containing 250:1 Microscint™-40 (Packard, Meriden, Conn.). The plates were heat-sealed (TopSeal™-P, Packard, Meriden, Conn.) according to the manufacturers directions and mixed for 30 min.

Radioactivity was measured on a microplate scintillation counter (TopCount, Packard, Meriden, Conn.). IC₅₀'s were determined as the concentration of inhibitor compound inhibiting transfer of [³H]CE from the supernatant [³H]CE-HDL to the precipitated VLDL and LDL by 50% compared to the transfer obtained in the control wells. The maximum percent transfer (in the control wells) was determined using the following equation: ${\% \quad {Transfer}} = \frac{\left\lbrack {{dpm}_{blank} - {dpm}_{control}} \right\rbrack \times 100}{{dpm}_{blank}}$

The percent of control transfer determined in the wells containing inhibitor compounds was determined as follows: ${\% \quad {Control}} = \frac{\left\lbrack {{dpm}_{blank} - {dpm}_{test}} \right\rbrack \times 100}{{dpm}_{blank} - {dpm}_{control}}$

IC₅₀ values were then calculated from plots of % control versus concentration of inhibitor compound. The IC₅₀ values of the substituted pyridine compounds determined by this method are as follows: Compound 7, 17 micromolar; Compound 180, 9 micromolar; Compound 181, 16 micromolar; Compound 214, 70 micromolar; and Compound 215, 110 micromolar.

EXAMPLE 56

Inhibition of CETP Activity In Vivo

Inhibition of CETP by a test compound can be determined by administering the compound to an animal by intravenous injection, determining the rate of transfer of tritium-labeled cholesteryl ester (³H]CE) from HDL to VLDL and LDL particles, and comparing the rate of transfer with the rate of transfer observed in control animals.

Male golden Syrian hamsters were maintained on a diet of chow containing 0.24% cholesterol for at least two weeks prior to the study. Immediately before the experiment, animals were anesthetized with pentobarbital. Anesthesia was maintained throughout the experiment. Indwelling catheters were inserted into the jugular vein and carotid artery. Test compound, Dimethyl 5,5′-dithiobis[2-difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate] (Compound 181), was dissolved as a 80 mM stock solution in vehicle (2% ethanol: 98% PEG 400, Sigma Chemical Company, St. Louis, Mo., USA). At the start of the experiment all animals received 0.2 ml of a solution containing [³H]-CE-HDL into the jugular vein. [³H[-CE-HDL is a preparation of human HDL containing tritium-labeled cholesteryl ester, and was prepared according to the method of Glenn et al. (“Quantification of Cholesteryl Ester Transfer Protein (CETP): A) CETP Activity and B) Immunochemical Assay of CETP Protein,” Meth. Enzymol., Glenn and Melton (Meth. Enzymol., 263, 339-351 (1996) which is incorporated herein by reference).

After 2 minutes, the animals received 0.1 ml of the test solution injected into the jugular vein. Control animals received 0.1 ml of the vehicle solution without test compound. After 5 minutes, the first blood samples (0.5 ml) were taken from the carotid artery and collected in standard microtainer tubes containing ethylenediamine tetraacetic acid. Saline (0.5 ml) was injected to flush the catheter and replace blood volume. Subsequent blood samples were taken at two hours and four hours by the same method. Blood samples were mixed well and kept on ice until the completion of the experiment.

Plasma was obtained by centrifugation of the blood samples at 4° C. The plasma (50 μl) was then treated with 5 μl of precipitating reagent (dextran sulfate, 10 g/l; 0.5M magnesium chloride to remove VLDL/LDL. After centrifugation, the resulting supernatant (25 μl) containing the HDL was analyzed for radioactivity using a liquid scintillation counter. The percentage [³H] CE transferred from HDL to LDL and VLDL (% transfer) was calculated based on the total radioactivity in equivalent serum samples before precipitation. Typically, the amount of transfer from HDL to LDL and VLDL in control animals was 30 to 35% after four hours. The polyethylene glycol vehicle was determined to have no effect on CETP activity in this model.

Table 14 shows the results of an experiment utilizing five animals that received Dimethyl 5,5′-dithiobis[2-difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate] (Compound 181), and five animals that received vehicle. At two hours, mean values of 13% [³H]-Ce transfer from HDL to LDL and VLDL were obtained for the control animals, but only 4.7% transfer for the animals receiving Compound 181. This represents a 64% inhibition of CETP activity. Student t-tests were performed to determine if the means for control and animals treated with Compound 181 were statistically different. Values of p<0.01 for both sets of data indicate that the differences are highly significant.

TABLE 14 % Transfer % Inhibition Compound Compound Control 181 181 t-Test Two Hours 13 4.7 63.6 0.008 Four hours 21.6 10.6 50.8 0.001

Similarly, in separate experiments a mean of 21.6% [³H]-CE transfer was obtained for the control animals at four hours, but only 10.6% was transferred in animals treated with methyl 2-(difluoromethyl)-5-mercapto-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (Compound 7), representing a 50% inhibition of CETP activity.

EXAMPLE 57

Chronic Inhibition of CETP Activity In Vivo

Chronic inhibition of CETP can be achieved by administration of Dimethyl 5,5′-dithiobis[2-difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate] (Compound 181) to hamsters using Alzet pump delivery of Compound 181 into the jugular veins of hamsters. Inhibition of CETP should lead to an increase in HDL cholesterol with a concomitant decrease in LDL cholesterol. This can be determined by filtering serum obtained at different time intervals after initiation of inhibitor infusion and quantitating the amount of cholesterol in the LDL and HDL peaks, respectively. In addition the activity of CETP in the serum can be assessed in an ex vivo CETP activity assay.

Male golden Syrian hamsters were maintained on a diet of normal rodent chow enriched with 0.24% cholesterol for at least 2 weeks prior to study. On Day 1, the hamsters were anesthetized with pentobarbital. An indwelling catheter was inserted into the jugular vein and exteriorized onto the back of the neck. The hamsters received 100 μ of Compound 181 (38.5 mg/kg) in a 2% ethanol:98% PEG400 vehicle, or the 2% ethanol:98% PEG400 vehicle alone. An Alzet pump was then attached to the jugular catheter which delivered a steady infusion of 24 μl/day for a dose of 1.3 mg/day(9.2 mg/kg/day). The hamsters received the vehicle (2% ETOH:98% PEG400) or Compound 181 for 8 days. The hamsters were maintained for 12 days. Blood samples were taken on day 1 (pre-bleed) at the time of surgery, and on days 5, 7, 8 and 12. Fast Protein Liquid Chromatography (FPLC) on tandem Superose 6 columns of pooled hamster serum was performed to obtain cholesterol profiles for the two experimental groups.

Table 15 shows the results of an experiment utilizing 5 hamsters in each group, vehicle and Compound 181. Serum cholesterol profiles were determined on pooled sera from each group. Total serum cholesterol and CETP activity were determined on individual serum samples. In hamsters administered Compound 181 chronically, there was a 30% reduction and 26% increase in LDL cholesterol and HDL cholesterol concentrations, respectively, compared to the vehicle group at Day 5. The decrease in LDL and increase in HDL persisted until Day 8 when the Alzet pump was exhausted. At Day 12, LDL cholesterol concentrations began to rise and HDL cholesterol concentrations started to decrease toward the concentrations in the vehicle group (90% and 114% of vehicle group, respectively). It should be noted that an average 10% reduction in CETP activity was determined by ex vivo assay on Days 5 and 8 with a return to vehicle control level by day 12. Therefore, it would appear that for every percent reduction in CETP activity determined by the ex vivo assay, there was a 2-3% decrease in LDL cholesterol or increase in HDL cholesterol concentrations.

TABLE 15 Cholesterol Concentrations In Compound 181 % Cholesterol Concentration In Vehicle Group DAY LDL HDL Day 1 111% 105% Day 5  70% 126% Day 8  75% 115% Day 12  90% 114%

The foregoing biological data demonstrate that administration of the substituted pyridine inhibitors of the present invention produces inhibition of CETP-mediated lipid transfer in vivo.

All mentioned references are incorporated by reference as if here written.

In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As various changes could be made in the above compositions and processes without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense. 

What is claimed is:
 1. A method for inhibiting the activity of cholesteryl ester transfer protein in vivo by administering to a subject a therapeutically-effective amount of a compound, a tautomer of the compound, or a pharmaceutically-acceptable salt of the compound or tautomer, wherein: the compound corresponds in structure to Formula I:

R₂ and R₆ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, fluorinated aralkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; at least one of R₂ and R₆ is fluorinated alkyl, chlorofluorinated alkyl, or alkoxyalkyl; R₃ is selected from the group consisting of amido, arylcarbonyl, heteroarylcarbonyl, —CHO, and —CO₂R₇; R₇ is selected from the group consisting of hydrogen, alkyl, and cyanoalkyl; R₄ is selected from the group consisting of thiol, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, cycloalkylthio, cycloalkenylthio, and —SO₂R₉; R₉ is selected from the group consisting of hydroxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; R₅ is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylcarbonyloxyalkyl, alkenylcarbonyloxyalkyl, alkynylcarbonyloxyalkyl, arylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl, heterocyclylcarbonyloxyalkyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl (other than δ-lactone-alkyl), cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl (other than δ-lactone-alkenyl), alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, alkoxyalkyl, alkenoxyalkyl, alkynoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, heterocyclyloxyalkyl, alkoxyalkenyl, alkenoxyalkenyl, alkynoxyalkenyl, aryloxyalkenyl, heteroaryloxyalkenyl, heterocyclyloxyalkenyl, cyano, hydroxymethyl, —CO₂R₁₄,

R₁₄ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; R_(15b) is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, heterocyclylthio, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, aroyloxy, and alkylsulfonyloxy; R_(16b) is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, arylalkoxy, and trialkylsilyloxy; R₁₇ and R₁₈ are independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; R₁₉ is selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —SR₂₀, —OR₂₁, and —R₂₂CO₂R₂₃; R₂₀ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminoaryl, aminoheteroaryl, aminoheterocyclyl, alkylheteroarylamino, and arylheteroarylamino; R₂₁ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; R₂₂ is selected from the group consisting of alkylene and arylene; R₂₃ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; R₂₄ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, aralkenyl, and aralkynyl; R₂₅ is heterocyclylidenyl; R₂₆ and R₂₇ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; R₂₈ and R₂₉ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; R₃₀ and R₃₁ are independently selected from the group consisting of alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy; R₃₂ and R₃₃ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; each R₃₆ is independently selected from the group consisting of alkyl, alkenyl, aryl, heteroaryl, and heterocyclyl; R₃₇ and R₃₈ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; R₃₉ is selected from the group consisting of hydrogen, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, and heterocyclylthio; R₄₀ is selected from the group consisting of haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, cycloalkyl, cycloalkenyl, heterocyclylalkoxy, heterocyclylalkenoxy, heterocyclylalkynoxy, alkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, and heterocyclylthio; R₄₁ is heterocyclylidenyl; R₄₂ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; R₄₃ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, and haloheterocyclyl; R₄₄ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; R₄₅ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, haloheterocyclyl, heterocyclyl, cycloalkylalkyl, cycloalkenylalkyl, aralkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, aralkenyl, heteroarylalkenyl, heterocyclylalkenyl, alkylthioalkyl, alkenylthioalkyl, alkynylthioalkyl, arylthioalkyl, heteroarylthioalkyl, heterocyclylthioalkyl, alkylthioalkenyl, alkenylthioalkenyl, alkynylthioalkenyl, arylthioalkenyl, heteroarylthioalkenyl, heterocyclylthioalkenyl, aminocarbonylalkyl, aminocarbonylalkenyl, aminocarbonylalkynyl, aminocarbonylaryl, aminocarbonylheteroaryl, aminocarbonylheterocyclyl, —SR₄₆, and —CH₂R₄₇; R₄₆ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; R₄₇ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; R₄₈ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; R₄₉ is selected from the group consisting of alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, and haloheterocyclyl; R₅₀ is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, alkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and heterocyclyloxy; R₅₁ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, haloheteroaryl, and haloheterocyclyl; R₅₃ is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocyclyl; except to the extent otherwise stated, the term alkyl, alone or in combination with other terms, encompasses both unsubstituted and substituted alkyl; except to the extent otherwise stated, the term alkenyl, alone or in combination with other terms, encompasses both unsubstituted and substituted alkenyl; except to the extent otherwise stated, the term alkynyl, alone or in combination with other terms, encompasses both unsubstituted and substituted alkynyl; except to the extent otherwise stated, the term aryl, alone or in combination with other terms, encompasses both unsubstituted and substituted aryl; except to the extent otherwise stated, the term heteroaryl, alone or in combination with other terms, encompasses both unsubstituted and substituted heteroaryl; except to the extent otherwise stated, the term heterocyclyl, alone or in combination with other terms, encompasses both unsubstituted and substituted heterocyclyl; and except to the extent otherwise stated, the term cycloalkyl, alone or in combination with other terms, encompasses both unsubstituted and substituted cycloalkyl.
 2. The method of claim 1, wherein: R₂ and R₆ are independently selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, chlorofluorinated alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl; R₃ is selected from the group consisting of amido, arylcarbonyl, heteroarylcarbonyl, and —CO₂R₇; R₄ is selected from the group consisting of thiol, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, and —SO₂R₉; R₉ is aryl; R₅ is selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, haloalkyl, alkynyl, heterocyclyl, heteroaryl, alkoxy, aryloxy, arylcarbonyloxyalkyl, heterocyclylalkyl (other than δ-lactone-alkyl and heterocyclyl-ethyl), alkylthioalkyl, arylthioalkyl, heteroarylthioalkyl, alkoxyalkenyl, cyano, hydroxymethyl, —CO₂R₁₄,

R₁₄ is alkyl; R_(15b) is selected from the group consisting of hydroxy, hydrogen, halogen, alkylthio, and alkoxy; R_(16b) is selected from the group consisting of alkyl, aryl, and heteroaryl; R₁₇ and R₁₈ are independently selected alkyl; R₁₉ is selected from the group consisting of aryl, heteroaryl, —SR₂₀, —OR₂₁, and —R₂₂CO₂R₂₃; R₂₀ is selected from the group consisting of alkyl, aryl, and aminoalkyl; R₂₁ is aryl; R₂₂ is alkylene; R₂₃ is alkyl; R₂₄ is selected from the group consisting of hydrogen, unsubstituted alkyl, and aralkyl; R₂₆ and R₂₇ are independently selected alkyl; R₂₈ and R₂₉ are independently selected alkyl; R₃₀ and R₃₁ are independently selected alkoxy; R₃₂ is selected from the group consisting of hydrogen and alkyl; R₃₃ is alkyl; each R₃₆ is independently selected alkyl; R₃₇ and R₃₈ are independently selected alkyl; R₃₉ is selected from the group consisting of hydrogen, alkoxy, and alkylthio; R₄₀ is selected from the group consisting of haloalkyl, cycloalkyl, heterocyclylalkoxy, and alkylthio; R₄₂ is selected from the group consisting of hydrogen and alkyl; R₄₃ is selected from the group consisting of cycloalkyl, chlorinated alkyl, and substituted heteroaryl; R₄₄ is heteroaryl; R₄₅ is selected from the group consisting of hydrogen, alkyl, haloalkyl, heterocyclyl, aralkyl, heteroaralkyl, alkylthioalkyl, aminocarbonylalkyl, —SR₄₆, and —CH₂R₄₇; R₄₆ is selected from the group consisting of aryl and heteroaryl; R₄₇ is selected from the group consisting of aryl and heteroaryl; R₄₈ is selected from the group consisting of hydrogen and alkyl; R₄₉ is selected from the group consisting of alkoxy and haloalkyl; R₅₀ is selected from the group consisting of alkyl, alkoxy, aryl, and heteroaryl; R₅₁ is selected from the group consisting of haloalkyl and alkyl; and R₅₃ is aryl.
 3. The method of claim 1, wherein: when R₂ is difluoromethyl, R₃ is —CO₂CH₃, R₅ is

R₆ is trifluoromethyl, and R₁₉ is pyrazolyl, then: R₄ is selected from the group consisting of thiol, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, and alkylthioalkyl, trialkylsilyl, —OC(O)N(R₈)₂, —SO₂R₉; when R₂ is difluoromethyl, R₃ is —CO₂CH₃, R₅ is 2-(4,5-dihydro-oxazolyl), and R₆ is trifluoromethyl, then: R₄ is selected from the group consisting of thiol, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, and —SO₂R₉; when R₂ and R₆ are independently fluorinated methyl, R₃ is —CO₂R₇, R₅ is cyano, and R₇ is selected from the group consisting of hydrogen and alkyl, then: R₄ is selected from the group consisting of thiol, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, and —SO₂R₉; when R₂ is methyl, R₃ is —CO₂C₂H₅, R₅ is

R₆ is methyl, and R₂₄ is aralkyl, then: R₄ is selected from the group consisting of thiol, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, and —SO₂R₉; when R₂ is selected from the group consisting of methyl, difluoromethyl, and trifluoromethyl, R₃ is —CO₂CH₃, R₅ is hydrogen, and R₆ is selected from the group consisting of methyl and trifluoromethyl, then: R₄ is selected from the group consisting of thiol, alkylthio, arylthio, cycloalkylthio, heterocyclylthio, and —SO₂R₉; and when R₂ is trifluoromethyl, R₃ is selected from the group consisting of —CO₂H and —CO₂C₂H₅, R₅ is methyl, and R₆ is selected from the group consisting of hydrogen and trifluoromethyl, then: R₄ is selected from the group consisting of thiol, alkylthio, arylthio, cycloalkylthio, heterocyclylthio and —SO₂R₉.
 4. The method of claim 2, wherein: R₂ is selected from the group consisting of methyl and fluorinated methyl; R₃ is —CO₂R₇; and R₇ is selected from the group consisting of hydrogen, methyl, and ethyl.
 5. The method of claim 2, wherein: R₂ is fluorinated alkyl; R₃ is —CO₂R₇; R₇ is selected from the group consisting of hydrogen and alkyl; R₅ is selected from the group consisting of pyrrolyl,

R₆ is fluorinated alkyl.
 6. The method of claim 2, wherein: R₂ is fluorinated alkyl; R₃ is —CO₂R₇; R₇ is selected from the group consisting of hydrogen and alkyl; R₄ is alkylthio; R₅ is selected from the group consisting of:

R₆ is fluorinated alkyl.
 7. The method of claim 2, wherein: R₂ is selected from the group consisting of alkyl and fluorinated alkyl; R₃ is —CO₂R₇; R₇ is selected from the group consisting of hydrogen and alkyl; R₄ is selected from the group consisting of alkylthio, arylthio and —SO₂R₉; R₅ is selected from the group consisting of hydrogen, hydroxy, halogen, alkoxy, and aryloxy; and R₆ is selected from the group consisting of hydrogen, fluorinated alkyl, and alkoxycarbonyl.
 8. The method of claim 2, wherein: R₂ is fluorinated alkyl; R₃ is —CO₂R₇; R₄ is arylthio; R₅ is selected from the group consisting of alkyl, haloalkyl, alkynyl, heterocyclyl, heteroaryl, heterocyclylalkyl, arylcarbonyloxyalkyl, alkylthioalkyl, arylthioalkyl, heteroarylthioalkyl, alkoxyalkenyl, cyano,

R_(15b) is selected from the group consisting of hydroxy, alkylthio, and alkoxy; R_(16b) is selected from the group consisting of alkyl and heteroaryl; and R₆ is selected from the group consisting of hydrogen, fluorinated alkyl, and alkoxy.
 9. The method of claim 2, wherein: R₂ is selected from the group consisting of hydroxy, alkyl, fluorinated alkyl, and alkoxyalkyl; R₃ is selected from the group consisting of amido and —CO₂R₇; R₇ is selected from the group consisting of hydrogen and alkyl; R₄ is selected from the group consisting of thiol, alkylthio, cycloalkylthio, and heterocyclylthio; R₅ is CO₂R₁₄; and R₆ is selected from the group consisting of hydrogen, hydroxy, alkyl, fluorinated alkyl, and alkoxyalkyl.
 10. The method of claim 2, wherein: R₂ is selected from the group consisting of alkyl and fluorinated alkyl; R₃ is —CO₂R₇; R₇ is selected from the group consisting of hydrogen and alkyl; R₄ is selected from the group consisting of thiol, arylthio, and heterocyclylthio; R₅ is selected from the group consisting of alkyl, heterocyclyl, arylthioalkyl, heteroarylthioalkyl, —CO₂R₁₄,

R_(15b) is hydroxy; R_(16b) is heteroaryl; R₁₉ is —SR₂₀; R₂₀ is alkyl; R₃₉ is alkoxy; R₄₀ is haloalkyl; R₄₅ is selected from the group consisting of hydrogen, —SR₄₆, and —CH₂R₄₇; R₅₀ is selected from the group consisting of alkyl and alkoxy; and R₆ is selected from the group consisting of alkyl and fluorinated alkyl.
 11. The method of claim 2, wherein the compound is selected from the group consisting of 5 ethyl 3-methyl-2-(difluoromethyl)-4-[(4,5-dihydro-2-thiazolyl)thio]-6-(trifluoromethyl)-3,5-pyridinedicarboxylate; and methyl 4-(4-i-propylphenylthio)-5-methyl-6-(trifluoromethyl)-3-pyridinecarboxylate.
 12. The method of claim 1, wherein the compound corresponds in structure to the following formula:


13. The method of claim 1, wherein the compound corresponds in structure to a formula selected from the group consisting of:


14. The method of claim 1, wherein the compound corresponds in structure to a formula selected from the group consisting of: 